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Marszołek A, Leśniak M, Sekunda A, Siwek A, Skiba Z, Lejman M, Zawitkowska J. Haploidentical HSCT in the Treatment of Pediatric Hematological Disorders. Int J Mol Sci 2024; 25:6380. [PMID: 38928087 PMCID: PMC11204214 DOI: 10.3390/ijms25126380] [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: 04/26/2024] [Revised: 05/28/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent hematopoietic stem cell transplantation (HSCT) in the absence of an HLA-matched donor. Haploidentical HSCT (haplo-HSCT) can be an effective treatment for non-malignant pediatric disorders, such as primary immunodeficiencies or hemoglobinopathies, by enabling a much quicker selection of the appropriate donor for virtually all patients, low incidence of graft-versus-host disease (GVHD), and transplant-related mortality (TRM). Moreover, the outcomes of haplo-HSCT among children with hematological malignancies have improved radically. The most demanding tasks for clinicians are minimizing T-cell-mediated alloreactivity as well as early GVHD prevention. As a result, several T-cell depletion approaches, such as ex vivo T-cell depletion (TCD), and T-cell replete approaches, such as a combination of anti-thymocyte globulin (ATG), post-transplantation cyclophosphamide (PTCy), cyclosporine/tacrolimus, mycophenolate mofetil, or methotrexate, have been taken up. As more research is needed to establish the most beneficial form of therapy, haplo-HSCT is currently considered an alternative donor strategy for pediatric and adult patients with complications like viral and bacterial infections, invasive fungal disease, and GVHD.
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Affiliation(s)
- Anna Marszołek
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland; (A.M.); (M.L.); (A.S.); (A.S.); (Z.S.)
| | - Maria Leśniak
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland; (A.M.); (M.L.); (A.S.); (A.S.); (Z.S.)
| | - Anna Sekunda
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland; (A.M.); (M.L.); (A.S.); (A.S.); (Z.S.)
| | - Aleksander Siwek
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland; (A.M.); (M.L.); (A.S.); (A.S.); (Z.S.)
| | - Zuzanna Skiba
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland; (A.M.); (M.L.); (A.S.); (A.S.); (Z.S.)
| | - Monika Lejman
- Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Joanna Zawitkowska
- Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
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Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia. Blood Adv 2021; 6:339-357. [PMID: 34547770 PMCID: PMC8753217 DOI: 10.1182/bloodadvances.2021004916] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/05/2021] [Indexed: 11/20/2022] Open
Abstract
Haploidentical HCT is the preferred alternate donor approach for adults with ALL. Haploidentical transplantation had similar survival compared with fully HLA-matched donor HCT but with reduced GVHD. The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.
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Issels RD, Lindner LH, von Bergwelt-Baildon M, Lang P, Rischpler C, Diem H, Mosetter B, Eckl J, Schendel DJ, Salat C, Stötzer O, Burdach S, von Luettichau-Teichert I, Handgretinger R, Neumann J, Kirchner T, Steiger K, Boxberg M, Mansmann U, Multhoff G, Noessner E. Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma - a case report. Int J Hyperthermia 2020; 37:55-65. [PMID: 31918587 DOI: 10.1080/02656736.2019.1709666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Introduction: An abscopal effect is a clinical observation whereby a local treatment is associated with regression of metastatic cancer at a site distant from the primary location of treatment. Here, we describe the clinical systemic effect induced by regional hyperthermia combined with low-dose chemotherapy and provide immunologic correlates.Case presentation: A 15-year-old patient had been diagnosed with alveolar rhabdomyosarcoma (ARMS). All previous treatment options failed in the patient including haploidentical stem cell transplantation and donor lymphocyte infusion. The patient presented with local and metastatic disease, and upon admission, underwent regional hyperthermia combined with low-dose chemotherapy. Immediately following therapy severe skin reactions were observed. Skin biopsies revealed an intraepithelial lymphocytic infiltration dominated by CD3+/CD8+ T cells with a regular network of dendritic cells. Clinical images compared before and during sequential treatment cycles showed complete metabolic response of the local tumor for more than 10 months of therapy. In addition, metastases completely regressed although they were not direct targets of regional hyperthermia. The systemic effect was associated with enhanced frequency of NK cells and T cells expressing the lectin-like natural-killer group 2 D activating receptor (NKG2D), an increase of the CD56bright subset of NK cells, as well as an increase of effector/memory and effector CD8+ and CD4+ T cells in the blood while the percentage of CD25+FOXP3+ regulatory T cells declined.Conclusions: Regional hyperthermia combined with low-dose chemotherapy had the potential to create a systemic effect which was associated with activation of NK cells and T cells.
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Affiliation(s)
- Rolf D Issels
- Department of Medicine III, University Hospital, Munich, Germany
| | - Lars H Lindner
- Department of Medicine III, University Hospital, Munich, Germany
| | | | - Peter Lang
- Department of General Pediatrics, Hematology/Oncology, University Children's Hospital, Tuebingenthe, Germany
| | - Christoph Rischpler
- Department of Nuclear Medicine, Technical University Munich, Munich, Germany
| | - Heinz Diem
- Laboratory for Hematological Diagnostics, Gauting, Germany
| | - Barbara Mosetter
- Immunoanalytics Research Group - Tissue Control of Immunocytes & Core Facility, Helmholtz Center, Munich, Germany
| | | | | | - Christoph Salat
- Medical Center for Hematology and Oncology Munich, Munich, Germany
| | - Oliver Stötzer
- Medical Center for Hematology and Oncology Munich, Munich, Germany
| | - Stefan Burdach
- Department of Pediatrics and Children's Cancer Research Center, Technical University of Munich, Munich, Germany
| | | | - Rupert Handgretinger
- Department of General Pediatrics, Hematology/Oncology, University Children's Hospital, Tuebingenthe, Germany
| | | | | | - Katja Steiger
- Institute of Pathology, Technical University Munich, Munich, Germany
| | - Melanie Boxberg
- Institute of Pathology, Technical University Munich, Munich, Germany
| | - Ulrich Mansmann
- Institute of Biostatistics and Epidemiology, LMU, Munich, Germany
| | - Gabriele Multhoff
- Radiation Immune-Oncology Group, Center for Translational Cancer Research, Technical University Munich, Munich, Germany
| | - Elfriede Noessner
- Immunoanalytics Research Group - Tissue Control of Immunocytes & Core Facility, Helmholtz Center, Munich, Germany
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GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia. Blood Adv 2020; 3:1441-1449. [PMID: 31053571 DOI: 10.1182/bloodadvances.2018030171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/07/2019] [Indexed: 12/22/2022] Open
Abstract
We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.
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Zhang R, He Y, Yang D, Jiang E, Ma Q, Pang A, Zhai W, Wei J, Feng S, Han M. Combination treatment of rituximab and donor platelets infusion to reduce donor-specific anti-HLA antibodies for stem cells engraftment in haploidentical transplantation. J Clin Lab Anal 2020; 34:e23261. [PMID: 32112480 PMCID: PMC7370703 DOI: 10.1002/jcla.23261] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/13/2020] [Accepted: 01/28/2020] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) in recipients is a risk factor for donor stem cell graft failure in haploidentical hematopoietic stem cell transplantation (haplo-HSCT), and the treatment to reduce the levels of DSAs is not unanimous. This study was to analysis the role of DSAs for stem cell engraftment and to discuss the effective treatment to reduce DSAs in haplo-HSCT. METHODS We retrospectively evaluated the levels of DSAs and the effect of the combination treatment of rituximab and donor platelets (PLTs) for donor stem cell engraftment in haplo-HSCT patients from June 2016 to March 2018 at our center. RESULTS Nine patients (11.5%) out of the total 78 patients were DSAs-positive and multivariate analysis revealed DSAs was the only factor that affected engraftment. Seven out of the 9 DSAs (+) patients received therapy: Four had antibodies against donor HLA class I (HLA-I) antigens and were administered two therapeutic amounts of donor apheresis platelets (platelet count approximately 3-5 × 1011 ) before donor stem cell infusion and the other three patients received a combination therapy of donor apheresis platelets and rituximab due to the antibodies against both donor HLA-I antigens and HLA class II (HLA-II) antigens. All the seven patients achieved donor stem cell engraftment successfully, and the DSAs levels decreased rapidly after transplantation. CONCLUSIONS DSAs is an important factor affecting engraftment in haplo-HSCT. Donor platelet transfusion is one simple and effective treatment for HLA-I DSAs, and a combination therapy should be administered if patients have both HLA-I and HLA-II antibodies.
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Affiliation(s)
- Rongli Zhang
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Yi He
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Donglin Yang
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Erlie Jiang
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Qiaoling Ma
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Aiming Pang
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Weihua Zhai
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Jialin Wei
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Sizhou Feng
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
| | - Mingzhe Han
- Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin, China
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Wang Y, Huang XJ. [Advances in hematopoietic stem cell transplantation for hematological disease]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:704-708. [PMID: 31495146 PMCID: PMC7342883 DOI: 10.3760/cma.j.issn.0253-2727.2019.08.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Indexed: 11/05/2022]
Affiliation(s)
- Y Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing 100044, China
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Reisner Y, Or-Geva N. Veto cells for safer nonmyeloablative haploidentical HSCT and CAR T cell therapy. Semin Hematol 2019; 56:173-182. [PMID: 31202427 DOI: 10.1053/j.seminhematol.2019.03.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 03/18/2019] [Indexed: 12/15/2022]
Abstract
Haploidentical donors are a readily available source for mismatched hematopoietic bone marrow transplantation. The application of this regimen is constantly increasing with the advent of methods that overcome T-cell alloreactions that occur due to human-leukocyte-antigen disparity between host and donor. One successful method to overcome both graft rejection and graft-vs-host disease is transplantation of large numbers T-cell-depleted (TCD) haploidentical stem cell grafts (haploSCT), after myeloablative conditioning. The success of stem cell dose escalation is attributed to a unique immunoregulatory cell-property, termed "veto-activity." However, engraftment of mismatched hematopoietic stem cells following reduced-intensity conditioning still represents a major challenge. Here, we describe how the addition of post-transplant high-dose cyclophosphamide can promote immune tolerance induction after megadose TCD haploSCT, following nonmyeloablative conditioning. We also discuss ways of harnessing the immune regulatory properties of adoptively transferred "veto" cells to support mixed chimerism further and confer tolerance to cell-therapies, such as CAR-T cells. These approaches will soon be tested in phase 1-2 clinical studies and may prove to be a safe and efficacious treatment for many disorders such as hemoglobinopathies, autoimmune diseases, and as a prelude for organ tolerance. Moreover, this approach could pave the way for "off-the-shelf" cell-therapy agents, making them cheaper and easily obtainable.
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Affiliation(s)
- Yair Reisner
- Stem Cell Research, Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
| | - Noga Or-Geva
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Interdepartmental Program in Immunology, Stanford, TX
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Zhang RL, Zheng XH, Zhou LK, Zhang Y, Chen SL, Yang DL, Jiang EL, Wei JL, Huang Y, Ma QL, Zhai WH, Feng SZ, Han MZ, He Y. [Effects of preexisting donor-specific HLA antibodies for graft failure in un-manipulated haploidentical hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 39:190-195. [PMID: 29562462 PMCID: PMC7342994 DOI: 10.3760/cma.j.issn.0253-2727.2018.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
目的 探讨单倍体相合造血干细胞移植中HLA供者特异性抗体（DSA）对干细胞植入的影响以及处理方法。 方法 采用免疫磁珠液相芯片技术，对2016年6月至2017年5月拟行单倍体相合造血干细胞移植患者进行HLA抗体及DSA的检测，对已完成移植患者进行DSA与植入失败相关性分析，检测移植前后DSA水平，探索针对DSA的处理方法。 结果 共检测了92例拟行单倍体相合造血干细胞移植患者的HLA抗体，其中16例（17.4%）存在HLA抗体，6例（6.5%）DSA阳性。在常规清髓性预处理单倍体相合移植中，26例DSA阴性患者中有24例成功植入，仅有2例发生植入失败，而采用常规预处理的4例DSA阳性患者中仅有1例成功植入，其余3例发生植入失败，二组患者植入率差异有统计学意义[92.3%（24/26）对25.0%（1/4），χ2=8.433，P=0.004]。多因素分析显示，DSA是影响供者干细胞植入的唯一因素[OR=12.0（95% CI 1.39~103.5），P=0.024]。6例DSA阳性的患者中，4例次在移植时采取了针对DSA的措施，均获得供者干细胞顺利植入，其中3例HLA-Ⅰ类DSA阳性患者（首次移植2例、二次移植1例）在输入供者干细胞之前输入供者血小板，另1例HLA-Ⅰ、HLA-Ⅱ类DSA并存患者在二次移植时更换供者并给予全身放疗、利妥昔单抗及供者血小板输注。 结论 DSA是导致单倍体相合造血干细胞植入失败的关键因素，移植前应进行常规检查，DSA阳性患者应选用DSA阴性供者；无合适供者时，应采取适当措施降低DSA水平以促进干细胞植入。
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Affiliation(s)
- R L Zhang
- Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China
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Salzmann-Manrique E, Bremm M, Huenecke S, Stech M, Orth A, Eyrich M, Schulz A, Esser R, Klingebiel T, Bader P, Herrmann E, Koehl U. Joint Modeling of Immune Reconstitution Post Haploidentical Stem Cell Transplantation in Pediatric Patients With Acute Leukemia Comparing CD34 +-Selected to CD3/CD19-Depleted Grafts in a Retrospective Multicenter Study. Front Immunol 2018; 9:1841. [PMID: 30154788 PMCID: PMC6102342 DOI: 10.3389/fimmu.2018.01841] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 07/26/2018] [Indexed: 12/25/2022] Open
Abstract
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
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Affiliation(s)
- Emilia Salzmann-Manrique
- Department of Medicine, Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe-University, Frankfurt, Germany.,Pediatric Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Melanie Bremm
- Pediatric Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Sabine Huenecke
- Pediatric Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Milena Stech
- Pediatric Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Andreas Orth
- University of Applied Sciences Frankfurt, Frankfurt, Germany
| | - Matthias Eyrich
- Pediatric Hematology and Oncology, University of Wuerzburg, Wuerzburg, Germany
| | - Ansgar Schulz
- Pediatric Hematology and Oncology, University of Ulm, Ulm, Germany
| | - Ruth Esser
- Institute of Cellular Therapeutics Hannover Medical School, Hannover, Germany
| | - Thomas Klingebiel
- Pediatric Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Peter Bader
- Pediatric Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Eva Herrmann
- Department of Medicine, Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Ulrike Koehl
- Institute of Cellular Therapeutics Hannover Medical School, Hannover, Germany.,Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany.,Fraunhofer Institute of Cellular Therapy and Immunology, Leipzig, Germany
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Busca A, Aversa F. In-vivo or ex-vivo T cell depletion or both to prevent graft-versus-host disease after hematopoietic stem cell transplantation. Expert Opin Biol Ther 2017; 17:1401-1415. [PMID: 28846051 DOI: 10.1080/14712598.2017.1369949] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Hematopoietic stem cell transplantation (HSCT) represents a widely accepted therapeutic strategy for the treatment of hematologic disorders which are otherwise considered incurable. Alloreactive T cells infused with the stem cell inoculum may generate graft-versus-host disease (GVHD) representing one the most relevant obstacles to the successful outcome of patients receiving allogeneic HSCT. Areas covered: In this review, the authors provide an overview of the most recent approaches of T-cell depletion (TCD) including ex-vivo αβ+ TCD and in-vivo TCD with anti-thymocyte globulin (ATG). Expert opinion: Ex vivo depletion of donor T-cells prevents both acute and chronic GVHD without the need for any additional posttransplant immunological prophylaxis either in haploidentical HSCT and HLA matched transplants. Three prospective trials evaluating the efficacy of ATG in matched unrelated donor transplant recipients demonstrated that ATG reduces the incidence of both acute and chronic GVHD without a significant increase of relapse rate, and similar results have been reported in the setting of blood stem cell grafts from matched sibling donors.
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Affiliation(s)
- Alessandro Busca
- a SSD Trapianto di Cellule Staminali , AOU Citta' della Salute e della Scienza , Torino , Italy
| | - Franco Aversa
- b Hematology and BMT Unit , University of Parma , Parma , Italy
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11
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Huenecke S, Bremm M, Cappel C, Esser R, Quaiser A, Bonig H, Jarisch A, Soerensen J, Klingebiel T, Bader P, Koehl U. Optimization of individualized graft composition: CD3/CD19 depletion combined with CD34 selection for haploidentical transplantation. Transfusion 2016; 56:2336-45. [DOI: 10.1111/trf.13694] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 05/04/2016] [Accepted: 05/07/2016] [Indexed: 11/30/2022]
Affiliation(s)
- Sabine Huenecke
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Melanie Bremm
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Claudia Cappel
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Ruth Esser
- GMP Development UnitInstitute of Cellular Therapeutics, IFB‐TX, Hannover Medical SchoolHannover Germany
| | - Andrea Quaiser
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Halvard Bonig
- Division for Cell ProcessingInstitute for Transfusion Medicine and Immunohematology, Goethe‐University Frankfurt/Main
- German Red Cross Blood Donor Service, Baden‐Württemberg‐HessenFrankfurt/Main, Germany
| | - Andrea Jarisch
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Jan Soerensen
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Thomas Klingebiel
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Peter Bader
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
| | - Ulrike Koehl
- Clinic for Pediatric and Adolescent MedicineUniversity HospitalFrankfurt Germany
- GMP Development UnitInstitute of Cellular Therapeutics, IFB‐TX, Hannover Medical SchoolHannover Germany
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12
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Im HJ, Koh KN, Seo JJ. Recent advances in haploidentical hematopoietic stem cell transplantation using ex vivo T cell-depleted graft in children and adolescents. Blood Res 2016; 51:8-16. [PMID: 27104186 PMCID: PMC4828537 DOI: 10.5045/br.2016.51.1.8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 03/11/2016] [Accepted: 03/16/2016] [Indexed: 12/21/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for children and adolescents with various malignant and non-malignant diseases. While human leukocyte antigen (HLA)-identical sibling donor is the preferred choice, matched unrelated volunteer donor is another realistic option for successful HSCT. Unfortunately, it is not always possible to find a HLA-matched donor for patients requiring HSCT, leading to a considerable number of deaths of patients without undergoing transplantation. Alternatively, allogeneic HSCT from haploidentical family members could provide donors for virtually all patients who need HSCT. Although the early attempts at allogeneic HSCT from haploidentical family donor (HFD) were disappointing, recent advances in the effective ex vivo depletion of T cells or unmanipulated in vivo regulation of T cells, better supportive care, and optimal conditioning regimens have significantly improved the outcomes of haploidentical HSCT. The ex vivo techniques used to remove T cells have evolved from the selection of CD34+ hematopoietic stem cell progenitors to the depletion of CD3+ cells, and more recently to the depletion of αβ+ T cells. The recent emerging evidence for ex vivo T cell-depleted haploidentical HSCT has provided additional therapeutic options for pediatric patients with diseases curable by HSCT but has not found a suitable related or unrelated donor. This review discusses recent advances in haploidentical HSCT, focusing on transplant using ex vivo T cell-depleted grafts. In addition, our experiences with this novel approach for the treatment of pediatric patients with malignant and non-malignant diseases are described.
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Affiliation(s)
- Ho Joon Im
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea
| | - Kyung-Nam Koh
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea
| | - Jong Jin Seo
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea
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13
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Rubio MT, Savani BN, Labopin M, Piemontese S, Polge E, Ciceri F, Bacigalupo A, Arcese W, Koc Y, Beelen D, Gülbas Z, Wu D, Santarone S, Tischer J, Afanasyev B, Schmid C, Giebel S, Mohty M, Nagler A. Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol 2016; 9:25. [PMID: 26980295 PMCID: PMC4791867 DOI: 10.1186/s13045-016-0248-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/24/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown. METHODS We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria. RESULTS A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94). CONCLUSIONS These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.
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Affiliation(s)
- Marie T Rubio
- Service d'Hématologie et de Thérapie cellulaire, Saint Antoine Hospital, Paris, France. .,INSERM UMR 938, Paris, France. .,Université Pierre et Marie Curie, Paris, France. .,Acute Leukemia Working Party of EBMT, Paris, France.
| | - Bipin N Savani
- Acute Leukemia Working Party of EBMT, Paris, France.,Vanderbilt University Medical Center, Nashville, TN, USA
| | - Myriam Labopin
- Service d'Hématologie et de Thérapie cellulaire, Saint Antoine Hospital, Paris, France.,INSERM UMR 938, Paris, France.,Université Pierre et Marie Curie, Paris, France.,Acute Leukemia Working Party of EBMT, Paris, France.,EBMT Paris study office/CEREST-TC, Paris, France
| | - Simona Piemontese
- Acute Leukemia Working Party of EBMT, Paris, France.,Ospedale San Raffaele s.r.l., Ematologia, Milan, Italy
| | - Emmanuelle Polge
- Service d'Hématologie et de Thérapie cellulaire, Saint Antoine Hospital, Paris, France.,INSERM UMR 938, Paris, France.,Université Pierre et Marie Curie, Paris, France.,Acute Leukemia Working Party of EBMT, Paris, France.,EBMT Paris study office/CEREST-TC, Paris, France
| | - Fabio Ciceri
- Ospedale San Raffaele s.r.l., Ematologia, Milan, Italy
| | | | - William Arcese
- Rome Transplant Network, Stem Cell Transplant Unit, Tor Vergata University, Rome, Italy
| | - Yener Koc
- Stem Cell Transplant Unit, Medical Park Hospitals, Antalya, Turkey
| | - Dietrich Beelen
- Department of Bone Marrow Transplantation, University Hospital, Essen, Germany
| | - Zafer Gülbas
- Bone Marrow Transplantation Department, Anadolu Medical Center Hospital, Kocaeli, Turkey
| | - Depei Wu
- Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China
| | | | - Johanna Tischer
- Department of Internal Medicine III, Ludwig-Maximilians-University Hospital of Munich-Grosshadern, Munich, Germany
| | - Boris Afanasyev
- SPb State I. Pavlov Medical University, St. Petersburg, Russia
| | | | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Hemato-Oncology, Cancer Center, Gliwice, Poland
| | - Mohamad Mohty
- Service d'Hématologie et de Thérapie cellulaire, Saint Antoine Hospital, Paris, France.,INSERM UMR 938, Paris, France.,Université Pierre et Marie Curie, Paris, France.,Acute Leukemia Working Party of EBMT, Paris, France.,EBMT Paris study office/CEREST-TC, Paris, France
| | - Arnon Nagler
- Université Pierre et Marie Curie, Paris, France.,Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel
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14
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Review on Haploidentical Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies. Adv Hematol 2016; 2016:5726132. [PMID: 27034676 PMCID: PMC4789357 DOI: 10.1155/2016/5726132] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 01/24/2016] [Indexed: 12/21/2022] Open
Abstract
Allogenic hematopoietic cell transplantation (HSCT) is typically the preferred curative therapy for adult patients with acute myeloid leukemia, but its use has been reduced as a consequence of limited donor availability in the form of either matched-related donors (MRD) or matched-unrelated donors (MUD). Alternative options such as unrelated umbilical cord blood (UCB) transplantation and haploidentical HSCT have been increasingly studied in the past few decades to overcome these obstacles. A human leukocyte antigen- (HLA-) haploidentical donor is a recipient's relative who shares an exact haplotype with the recipient but is mismatched for HLA genes on the unshared haplotype. These dissimilarities pose several challenges to the outcomes of the patient receiving such a type of HSCT, including higher rates of bidirectional alloreactivity and graft failure. In the past 5 years, however, several nonrandomized studies have shown promising results in terms of graft success and decreased rates of alloreactivity, in part due to newer grafting techniques and graft-versus-host disease (GVHD) prophylaxis. We present here a summary and review of the latest results of these studies as well as a brief discussion on the advantages and challenges of haploidentical HSCT.
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15
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Improved immune recovery after transplantation of TCRαβ/CD19-depleted allografts from haploidentical donors in pediatric patients. Bone Marrow Transplant 2016; 50 Suppl 2:S6-10. [PMID: 26039210 DOI: 10.1038/bmt.2015.87] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αβ T- and B-cell-depleted allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαβ and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/μL, >200 CD19+ cells/μL and >200 CD56+ cells/μL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/μL), for CD3+4+ at day +30 (58 vs 11 cells/μL) and for CD56+ at day +14 (622 vs 27 cells/μL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
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16
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Elmahdi S, Muramatsu H, Narita A, Torii Y, Ismael O, Kawashima N, Okuno Y, Sekiya Y, Xu Y, Wang X, Hama A, Ito Y, Takahashi Y, Kojima S. Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. Pediatr Transplant 2016; 20:105-13. [PMID: 26518333 DOI: 10.1111/petr.12620] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/16/2015] [Indexed: 11/29/2022]
Abstract
We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II-IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II-IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse.
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Affiliation(s)
- Shaimaa Elmahdi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Narita
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuka Torii
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Olfat Ismael
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nozomu Kawashima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Okuno
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuko Sekiya
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yinyan Xu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xinan Wang
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Asahito Hama
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Ito
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seiji Kojima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
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17
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Donor Specific Anti-HLA Antibody and Risk of Graft Failure in Haploidentical Stem Cell Transplantation. Adv Hematol 2016; 2016:4025073. [PMID: 26904122 PMCID: PMC4745275 DOI: 10.1155/2016/4025073] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 12/22/2015] [Indexed: 01/09/2023] Open
Abstract
Outcomes of allogeneic hematopoietic stem cell transplantation (AHSCT) using HLA-half matched related donors (haploidentical) have recently improved due to better control of alloreactive reactions in both graft-versus-host and host-versus-graft directions. The recognition of the role of humoral rejection in the development of primary graft failure in this setting has broadened our understanding about causes of engraftment failure in these patients, helped us better select donors for patients in need of AHSCT, and developed rational therapeutic measures for HLA sensitized patients to prevent this unfortunate event, which is usually associated with a very high mortality rate. With these recent advances the rate of graft failure in haploidentical transplantation has decreased to less than 5%.
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18
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Brodszki N, Turkiewicz D, Toporski J, Truedsson L, Dykes J. Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. Orphanet J Rare Dis 2016; 11:5. [PMID: 26768987 PMCID: PMC4714422 DOI: 10.1186/s13023-016-0385-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 01/10/2016] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for severe combined immunodeficiency (SCID); although, there is a high incidence of severe infections and an increased risk of graft-versus host-disease (GvHD) with HSCT. Early intervention is a crucial prognostic factor and a HLA-haploidentical parental donor is often available. Haploidentical HSCT protocols utilizing extensively ex vivo T-cell depleted grafts (CliniMACs system) have proven efficient in preventing GvHD, but cause a delay in early T-cell recovery that increases the risk of viral infections. Here, we present a novel approach for treating SCID that combines selective depletion of GvHD-inducing alpha/beta (α/β) T-cells from the haploidentical HSCT graft with a subsequent donor lymphocyte infusion (DLI) enriched for CD45RO+ memory T-cells. RESULTS Our patient was diagnosed with SCID (T-B + NK+ phenotype). At 9 months of age, he received a T cell receptor(TCR)α/β-cell depleted graft from his haploidentical mother, following a reduced intensity conditioning regimen with no additional GvHD prophylaxis. Engraftment was rapid with complete donor chimerism and no signs of GvHD. However, at 12 weeks post HSCT, the patient was still T-cell lymphopenic with clinical symptoms of multiple severe viral infections. Consequently, therapeutic DLIs were initiated for enhanced anti-viral immunity. The patient was treated with CD45RA+ depleted haploidentical maternal donor lymphocytes enriched from unmobilized whole blood, and a total T-cell dose of no more than 25 x10(3) CD3+ cells/kg with >99.9% purity of CD3 + CD45RO+ memory T-cells was transferred. Following the DLI, a prompt increase in CD3 + CD4+ and CD3 + CD8+ counts was observed with a subsequent clearance of viral infections. No acute or chronic GvHD was observed. CONCLUSIONS Automated depletion of CD45RA+ naïve T-cells from unmobilized whole blood is a simple and rapid strategy to provide unmanipulated DLIs, with a potentially broad repertoire of pathogen specific memory T-cells. In the haploidentical setting, CD45RA+ depleted DLIs can be safely administered at low T-cell doses for efficient enhancement of viral immunity and limited risk of GvHD. We demonstrate the successful use of this approach following TCR-α/β-cell depleted HSCT for the treatment of SCID.
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Affiliation(s)
| | | | - Jacek Toporski
- Children's Hospital, Skåne University Hospital, Lund, Sweden.
| | - Lennart Truedsson
- Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund, Sweden.
| | - Josefina Dykes
- Department of Laboratory Medicine, Section of Haematology and Transfusion Medicine, Lund University, Lund, Sweden.
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19
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Bremm M, Cappel C, Erben S, Jarisch A, Schumm M, Arendt A, Bonig H, Klingebiel T, Koehl U, Bader P, Huenecke S. Generation and flow cytometric quality control of clinical-scale TCRαβ/CD19-depleted grafts. CYTOMETRY PART B-CLINICAL CYTOMETRY 2015; 92:126-135. [DOI: 10.1002/cyto.b.21328] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 09/16/2015] [Accepted: 09/17/2015] [Indexed: 01/08/2023]
Affiliation(s)
- Melanie Bremm
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
| | - Claudia Cappel
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
| | - Stephanie Erben
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
| | - Andrea Jarisch
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
| | - Michael Schumm
- Department of Hematology/Oncology; Children's University Hospital; Tübingen Germany
| | | | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, Division for Cell Processing, German Red Cross Blood Donor Service Baden-Württemberg-Hessen; Frankfurt/Main Germany
| | - Thomas Klingebiel
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
| | - Ulrike Koehl
- Institute of Cellular Therapeutics, GMP Development Unit; IFB-TX; Hannover Medical School; Hannover Germany
| | - Peter Bader
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
| | - Sabine Huenecke
- Clinic for Pediatric and Adolescent Medicine; University Hospital; Frankfurt Germany
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20
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Chen Y, Huang XJ, Liu KY, Chen H, Chen YH, Zhang XH, Wang FR, Han W, Wang JZ, Wang Y, Yan CH, Zhang YY, Sun YQ, Xu LP. Infusion-related febrile reaction after haploidentical stem cell transplantation in children is associated with higher rates of engraftment syndrome and acute graft-versus-host disease. Pediatr Transplant 2015; 19:918-24. [PMID: 26332180 DOI: 10.1111/petr.12586] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/23/2015] [Indexed: 12/23/2022]
Abstract
The clinical significance and prognostic impact of IRFR in pediatric recipients of haploidentical SCT are not clearly understood. Therefore, we attempted to determine how IRFR affects clinical outcomes in children. Clinical data from 100 consecutive pediatric patients (60 boys and 40 girls; median age, 12 yr [range, 2-18 yr] after haploidentical SCT between January 2010 and December 2012 were collected retrospectively. IRFR was described as unexplained fever (>38 °C) within 24 h after the infusion of haploidentical PBSCs. Thirty-eight (38.0%) cases met the criteria for IRFR. ES was found in 24 (63.2%) of the 38 children with IRFR, with the median time of developing ES of +9 (7-16) days, while only 15 (25.4%) of the 59 children without IRFR were found with ES (p < 0.001). Similarly, the cumulative incidence rates of grade II-IV aGVHD were 50.0% in the IRFR group and 29.3% (p = 0.012) in the non-febrile group. Multivariate analysis identified IRFR as the risk factor for ES and aGVHD. In the haploidentical setting, IRFR is associated with the development of ES and aGVHD. We attempted to determine how IRFR affects clinical outcomes in children after haploidentical SCT. Thirty-eight children comprised the IRFR group, and 59 were in the control (non-IRFR) group. High incidence of ES was observed in children with the occurrence of IRFR. Similarly, the incidence of stage I-IV and II-IV aGVHD was significantly higher in the febrile group. Multivariate analysis showed IRFR to be the risk factor for ES and aGVHD.
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Affiliation(s)
- Yao Chen
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Huan Chen
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yu-Hong Chen
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Feng-Rong Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Wei Han
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Jing-Zhi Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Chen-Hua Yan
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yuan-Yuan Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yu-Qian Sun
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
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21
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Abstract
Allogeneic blood or bone-marrow transplantation (alloBMT) is a potentially curative treatment for a variety of haematological malignancies and nonmalignant diseases. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with alloBMT using other donors. Although only approximately one-third of patients have an HLA-matched sibling, nearly all patients have HLA-haploidentical related donors. Early studies using HLA-haploidentical alloBMT resulted in unacceptably high rates of graft rejection and graft-versus-host disease (GVHD), leading to high nonrelapse mortality and consequently poor survival. Several novel approaches to HLA-haploidentical alloBMT have yielded encouraging results with high rates of successful engraftment, effective GVHD control and favourable outcomes. In fact, outcomes of several retrospective comparative studies seem similar to those seen using other allograft sources, including those of HLA-matched-sibling alloBMT. In this Review, we provide an overview of the three most-developed approaches to HLA-haploidentical alloBMT: T-cell depletion with 'megadose' CD34(+) cells; granulocyte colony-stimulating factor-primed allografts combined with intensive pharmacological immunosuppression, including antithymocyte globulin; and high-dose, post-transplantation cyclophosphamide. We review the preclinical and biological data supporting each approach, results from major clinical studies, and completed or ongoing clinical studies comparing these approaches with other alloBMT platforms.
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22
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Refinement of treatment strategies in ex vivo T-cell-depleted haploidentical SCT for pediatric patients. Bone Marrow Transplant 2014; 50:225-31. [DOI: 10.1038/bmt.2014.232] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 08/25/2014] [Accepted: 09/01/2014] [Indexed: 12/17/2022]
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23
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Lang P, Teltschik HM, Feuchtinger T, Müller I, Pfeiffer M, Schumm M, Ebinger M, Schwarze CP, Gruhn B, Schrauder A, Albert MH, Greil J, Urban C, Handgretinger R. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia. Br J Haematol 2014; 165:688-98. [PMID: 24588540 DOI: 10.1111/bjh.12810] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 01/22/2014] [Indexed: 11/28/2022]
Abstract
Transplantation of T- and B-cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome (n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation (SCT). Toxicity-reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 10⁹/l leucocytes, >20 × 10⁹/l platelets and >0·1 × 10⁹/l T-cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft-versus-host disease (GvHD) grade II and III-IV occurred in 20% and 7%, chronic GvHD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant-related mortality (TRM) was 8% at one year and 20% at 5 years. Event-free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor.
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Affiliation(s)
- Peter Lang
- Children's University Hospital, University of Tuebingen, Tuebingen, Germany
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Abstract
Today human leukocyte antigen-haploidentical transplantation is a feasible option for patients with high-risk acute leukemia who do not have matched donors. Whether it is T-cell replete or T-cell depleted, it is still, however, associated with issues of transplant-related mortality and posttransplant leukemia relapse. After reports that adoptive immunotherapy with T-regulatory cells controls the alloreactivity of conventional T lymphocytes in animal models, tomorrow’s world of haploidentical transplantation will focus on new “designed” grafts. They will contain an appropriate ratio of conventional T lymphocytes and T-regulatory cells, natural killer cells, γ δ T cells, and other accessory cells. Preliminary results of ongoing clinical trials show the approach is feasible. It is associated with better immune reconstitution and a quite powerful graft-versus-leukemia effect with a low incidence of graft-versus-host disease and no need for posttransplant pharmacological prophylaxis. Future strategies will focus on enhancing the clinical benefit of T-regulatory cells by increasing their number and strengthening their function.
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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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26
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Sun Y, Xu L, Liu D, Zhang X, Han W, Wang Y, Chen H, Chen Y, Wang F, Wang J, Ji Y, Tang F, Liu K, Huang XJ. Incidence of invasive fungal disease after unmanipulated haploidentical stem cell transplantation was significantly higher than that after HLA-matched sibling transplantation. Clin Microbiol Infect 2013; 19:1029-34. [DOI: 10.1111/1469-0691.12120] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 11/02/2012] [Accepted: 11/25/2012] [Indexed: 01/21/2023]
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27
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Im HJ, Koh KN, Choi ES, Jang S, Kwon SW, Park CJ, Chi HS, Seo JJ. Excellent Outcome of Haploidentical Hematopoietic Stem Cell Transplantation in Children and Adolescents with Acquired Severe Aplastic Anemia. Biol Blood Marrow Transplant 2013; 19:754-9. [DOI: 10.1016/j.bbmt.2013.01.023] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 01/28/2013] [Indexed: 12/24/2022]
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Abstract
Haplotype-mismatched transplantation offers a unique opportunity to treat patients without a suitable matched related or unrelated donor. Indeed, related haplo-donors are usually extremely motivated, immediately available, and can provide additional stem or immune cells when required, a most important feature in the context of high-risk malignancies. Immunomagneticallly selected CD34(+) stem cell grafts enable rapid and sustained trilineage engraftment. However, the associated delay in immune reconstitution results in significant risk for severe infectious complications and malignant relapse. The infusion of T lymphocytes selectively depleted of their anti-host reactive components represents a most interesting approach to accelerate post-transplant T-cell recovery. Such a strategy relies on ex vivo donor cell activation against host antigens and their selective elimination. Immunotoxins and magnetic beads could target antigens such as CD25 with impressive results. Photodepletion of alloreactive T cells represents an appealing alternative to both eliminate anti-host immune T cells and spare resting T cells to fight infections. Interestingly, regulatory T cells can be retained after such treatment, and have been found to transform non-regulatory into regulatory T cells, a finding that may be of utmost importance in both prevention and control of graft-versus-host disease (GVHD). Efforts to promote efficient antigen presentation and selective allodepletion promise to accelerate immune reconstitution without GVHD and to address the most crucial issues in haplo-mismatched and other types of transplants.
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Affiliation(s)
- Jean-Philippe Bastien
- Division of Hematology and Stem Cell Transplantation, Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, Université de Montréal, Montreal, Canada
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29
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Abstract
Haploidentical transplantation opens the possibility to offer this treatment to a large number of patients with an otherwise incurable disease, such as some hematologic or oncologic malignancies, inborn or acquired bone marrow failure syndromes, hemoglobinopathies, immunodeficiencies, or other genetic diseases. Initial attempts at haploidentical transplantation using unmanipulated bone marrow were associated with a high transplant-related mortality. However, recent insights into the biology of haploidentical transplantation, the availability of effective in vivo large-scale graft-manipulation technology, and improved supportive care strategies have led to and are still leading to significantly better outcomes compared to previous decades. Methods for the in vitro depletion of T lymphocytes from mobilized peripheral blood stem cells (PBSC) to prevent graft-versus-host disease (GvHD) have facilitated the wider use and acceptance of haploidentical transplantation in children and adult patients. Besides in vitro T-cell depletion techniques, other methods, such as the isolation of alloreactive natural killer (NK) cells, virus-specific T lymphocytes, and other effector or regulatory cells are nowadays available to rapidly rebuild the immune system after haploidentical transplantation for the prevention of severe infections or relapses of the underlying diseases.
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Abstract
The feasibility of stem cell transplantation across the major histocompatibility barrier-as in haploidentical stem cell transplantation-has been proved for some time in several studies. The main limitations include a higher graft failure rate, delayed immune reconstitution after transplantation with high rates of life-threatening infections, a higher incidence of post-transplant lymphoproliferative disease, and severe acute and chronic graft-versus-host disease. In an attempt to reduce the transplant-related morbidity/mortality, several techniques had been evaluated involving conditioning regimen intensity, graft engineering, post-transplant cellular therapy and immunosuppression. This review will describe the current situation. It will also discuss initiatives and strategies to overcome the limitations associated with transplant across the MHC barrier.
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Affiliation(s)
- Amr Ahmed Nassar
- King Abdullah Medical City, Mecca, Western Province, Saudi Arabia.
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31
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Zhang C, Zhang X, Chen XH. Cellular mechanism for granulocyte-colony stimulating factor in the prevention of graft-versus-host disease in combined bone marrow and peripheral blood transplantation for hematological malignancies: the composition in collection. Transfus Apher Sci 2012; 48:3-9. [PMID: 23279971 DOI: 10.1016/j.transci.2012.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2011] [Accepted: 08/16/2012] [Indexed: 01/29/2023]
Abstract
Despite improvements in transplant immunology and clinical and supportive care, acute graft-versus-host disease (aGVHD) remains a clinical challenge and a major cause of morbidity and mortality for patients after allogeneic hematopoietic stem cell transplantation (HSCT). Many ways have been used to prevent and treat aGVHD, however, long-term survival remains poor. The key to improve aGVHD outcomes may, in fact, rest upon successful initial therapy. The HLA-matched HSCT was limited by the shortage of suitable donors. Unmanipulated haploidentical/mismatched related transplantation with combined granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells and G-CSF-mobilized bone marrow as a stronger aGVHD inhibition and graft-versus-leukemia effect, has been developed as an alternative transplantation strategy for patients with hematologic malignancies for the advantage of immediate donor availability, ability to select the best of many relatives, controlled graft composition and immediate access to donor-derived cellular therapies if required after transplantation. G-CSF is a potent hematopoietic cytokine, which is produced by fibroblasts, monocytes, and endothelial cells. G-CSF regulates production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, maturation and is also involved in mobilization of granulocytes, stem and progenitor cells, which has an important role in this transplantation. In this article, we review the possible mechanism for this combined G-CSF-mobilized HSCT in the prevention of aGVHD. Monocytes, T cells, Tregs cells, DC, adhesive molecule, NK cell/KIR ligand mismatching and mesenchymal stem cells may be involved in this transplantation.
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Affiliation(s)
- Cheng Zhang
- Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China
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Aversa F, Martelli MF, Velardi A. Haploidentical Hematopoietic Stem Cell Transplantation With a Megadose T-Cell–Depleted Graft: Harnessing Natural and Adaptive Immunity. Semin Oncol 2012. [DOI: 10.1053/j.seminoncol.2012.09.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Dvorak CC, Gilman AL, Horn B, Oon CY, Dunn EA, Baxter-Lowe LA, Cowan MJ. Haploidentical related-donor hematopoietic cell transplantation in children using megadoses of CliniMACs-selected CD34(+) cells and a fixed CD3(+) dose. Bone Marrow Transplant 2012. [PMID: 23178543 DOI: 10.1038/bmt.2012.186] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We conducted a prospective phase II trial utilizing the CliniMACs system to perform CD34(+)-cell selection of PBSCs from haploidentical donors to evaluate engraftment and hematoimmunological reconstitution. In total, 21 children with hematological malignancies or nonmalignant conditions underwent conditioning with 1200 cGy TBI, thiotepa, fludarabine and Thymoglobulin. Patients received megadoses of CD34(+) cells (median: 22 × 10(6)/kg) with a fixed dose of 3 × 10(4)/kg CD3(+) cells/kg, and engraftment occurred in 90% with prompt recovery of neutrophils and platelets. Grade II acute GVHD (aGVHD) was seen in 32% (95% confidence interval (CI), 15-54%) of evaluable patients, there was no grade III-IV aGVHD, and chronic extensive GVHD was seen in 35% (95% CI, 17-59%) of patients. The estimated 2-year EFS was 62% (95% CI, 48-83%) with a median survivor follow-up of 49 months (range: 18-119 months). Patients with nonmalignant diseases had an estimated 2-year EFS of 100% (95% CI, 56-100%) and patients with malignancies in remission had an estimated 2-year EFS of 56% (95% CI, 22-89%). Megadose CD34(+) cells with a fixed CD3(+) cell dose from haploidentical related donors resulted in good outcomes for pediatric patients with nonmalignant diseases and those with malignant diseases transplanted in remission.
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Affiliation(s)
- C C Dvorak
- Department of Pediatrics, Division of Allergy, Immunology, and Blood and Marrow Transplant, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA 94143-1278, USA.
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34
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Palma J, Salas L, Carrión F, Sotomayor C, Catalán P, Paris C, Turner V, Jorquera H, Handgretinger R, Rivera GK. Haploidentical stem cell transplantation for children with high-risk leukemia. Pediatr Blood Cancer 2012; 59:895-901. [PMID: 22238059 DOI: 10.1002/pbc.24022] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Accepted: 11/03/2011] [Indexed: 11/08/2022]
Abstract
BACKGROUND The Chilean population is ethnically diverse, and more than 50% of children referred for hematopoietic stem cell transplantation (HSCT) lack a suitable donor. PROCEDURE To expand the donor pool, we assessed the feasibility, tolerance, and efficacy of using a haploidentical (HI) donor and a reduced-intensity conditioning regimen for high-risk pediatric leukemia. This study was facilitated by technology transfer from St. Jude Children's Research Hospital over the 2 preceding years. RESULTS Between March 2006 and April 2009, 10 patients (median age, 9.8 years) received T cell-depleted grafts at Calvo Mackenna Hospital in Santiago. Median cell doses were CD34+: 7.45 × 10(6)/kg (range, 4.00-20.20 × 10(6)/kg); CD3+: 0.88 × 10(5)/kg (0.11-1.35 × 10(5)/kg); and CD56+: 71.30 × 10(6)/kg (31.50-131.80 × 10(6)/kg). Nine patients experienced complete engraftment; six of the nine remain alive and clinically well 13-50 months post-HSCT. Three patients died after bone marrow relapse, while only one died of transplant-related causes. Virus reactivation was the main post-transplant complication: 5/10 had positive CMV PCR but none had CMV disease. One patient developed acute GvHD > grade II and only one had chronic GvHD. CONCLUSIONS HI-HSCT is feasible in our setting, offers a rational treatment option, and expands the donor pool significantly for children with high-risk leukemia in a developing country. This information is especially relevant to other ethnically diverse populations that are poorly represented in international donor registries.
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Affiliation(s)
- Julia Palma
- Bone Marrow Transplant Unit, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.
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35
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Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, Bosque D, Chen J, Rondon G, Alatrash G, Alousi A, Bashir Q, Korbling M, Qazilbash M, Parmar S, Shpall E, Nieto Y, Hosing C, Kebriaei P, Khouri I, Popat U, de Lima M, Champlin RE. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:1835-44. [PMID: 22796535 DOI: 10.1016/j.bbmt.2012.07.003] [Citation(s) in RCA: 198] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 07/03/2012] [Indexed: 10/28/2022]
Abstract
Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.
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Affiliation(s)
- Stefan O Ciurea
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
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36
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Geyer MB, Ricci AM, Jacobson JS, Majzner R, Duffy D, Ven C, Ayello J, Bhatia M, Garvin JH, George D, Satwani P, Harrison L, Morris E, Semidei-Pomales M, Schwartz J, Alobeid B, Baxter-Lowe LA, Cairo MS. T cell depletion utilizing CD34+ stem cell selection and CD3+ addback from unrelated adult donors in paediatric allogeneic stem cell transplantation recipients. Br J Haematol 2012; 157:205-19. [DOI: 10.1111/j.1365-2141.2012.09048.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 12/27/2011] [Indexed: 01/27/2023]
Affiliation(s)
- Mark B. Geyer
- Department of Medicine; Massachusetts General Hospital; Harvard Medical School; Boston; MA
| | | | | | | | - Deirdre Duffy
- Department of Pediatrics; New York Medical College; Valhalla; NY
| | - Carmella Ven
- Department of Pediatrics; New York Medical College; Valhalla; NY
| | - Janet Ayello
- Department of Pediatrics; New York Medical College; Valhalla; NY
| | | | | | | | | | - Lauren Harrison
- Department of Pediatrics; New York Medical College; Valhalla; NY
| | - Erin Morris
- Department of Pediatrics; New York Medical College; Valhalla; NY
| | | | - Joseph Schwartz
- Department of Pathology and Cell Biology; Columbia University; New York; NY
| | - Bachir Alobeid
- Department of Pathology and Cell Biology; Columbia University; New York; NY
| | - Lee Ann Baxter-Lowe
- Department of Surgery; University of California San Francisco; San Francisco; CA
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37
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Sun YQ, Xu LP, Liu DH, Zhang XH, Chen YH, Chen H, Ji Y, Wang Y, Han W, Wang JZ, Wang FR, Liu KY, Huang XJ. The incidence and risk factors of invasive fungal infection after haploidentical haematopoietic stem cell transplantation without in vitro T-cell depletion. Clin Microbiol Infect 2011; 18:997-1003. [PMID: 22085092 DOI: 10.1111/j.1469-0691.2011.03697.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In recent years, we have successfully established a novel method of haploidentical haematopoietic stem cell transplantation (HSCT) without in vitro T-cell depletion. This study was aimed at analysing the incidence and risk factors of invasive fungal infection (IFI) with this transplantation method. The study comprised 291 patients who had undergone haploidentical HSCT from 1 January 2007 to 31 December 2008. IFI was diagnosed according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group 2002 criteria, and only proven or probable cases of IFI were regarded as true cases. A total of 39 patients were documented as having IFI, including four proven cases and 35 probable cases. The median time of diagnosis was 26 days (range: 6-405 days) after transplantation. The cumulative incidence rates of IFI at 40 days, 1 year, 2 years and 3 years after transplantation were 8.25%, 13.1%, 13.4% and 13.4%, respectively. Multivariate analysis identified platelet engraftment time (>17 days) (p 0.027; hazard ratio (HR) 2.432; 95% CI 1.105-5.355), a high risk of underlying disease (p 0.001; HR 2.916; 95% CI 1.515-5.611) and grade III-IV acute graft-versus-host disease (p 0.019; HR 2.407; 95% CI 1.154-5.022) as risk factors for IFI. The incidence rates of IFI in patients with no, one, two or three risk factors at 3 years after transplantation were 4.48%, 7.86%, 29.6% and 23.1%, respectively. In conclusion, IFI is an important complication following haploidentical HSCT without in vitro T-cell depletion.
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Affiliation(s)
- Y-Q Sun
- Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation for the Treatment of Haematological Diseases, Beijing, China
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38
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Josefsen D, Forfang L, Dyrhaug M, Blystad AK, Stokke T, Smeland EB, Kvalheim G. Side population cells in highly enriched CD34-positive cells from peripheral blood progenitor cells identify an immature subtype of hematopoietic progenitor cells but do not predict time to engraftment in patients treated with high-dose therapy. Eur J Haematol 2011; 87:494-502. [DOI: 10.1111/j.1600-0609.2011.01681.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Abstract
For patients with hematologic malignancies at high risk of relapse who do not have matched donors, a suitable alternative stem cell source is the HLA-haploidentical 2 or 3-loci mismatched family donor who is readily available for nearly all patients. Transplantation across the major HLA barrier is associated with strong T-cell alloreactions, which were originally manifested as a high incidence of severe GVHD and graft rejection. The present review shows how these obstacles to successful transplantation were overcome in the last 15 years, making full haplotype-mismatched transplantation a clinical reality that provides similar outcomes to transplantation from matched unrelated donors. The review also discusses the advantages and drawbacks of current options for full haplotype-mismatched transplantation and highlights innovative approaches for re-building immunity after transplantation and improving survival.
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40
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Feasibility and outcome of haploidentical SCT in pediatric high-risk hematologic malignancies and Fanconi anemia in Uruguay. Bone Marrow Transplant 2011; 47:663-8. [DOI: 10.1038/bmt.2011.148] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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41
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Locatelli F, Vinti L, Palumbo G, Rossi F, Bertaina A, Mastronuzzi A, Bernardo ME, Rutella S, Dellabona P, Giorgiani G, Moretta A, Moretta L. Strategies to optimize the outcome of children given T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation. Best Pract Res Clin Haematol 2011; 24:339-49. [PMID: 21925087 DOI: 10.1016/j.beha.2011.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The most advanced frontier of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is represented by the use of an HLA-partially matched relative as donor. In this type of transplantation, donor-derived natural killer (NK) cells, which are alloreactive toward recipient cells, significantly contribute to the eradication of leukemia blasts. Alloreactive NK cells may also kill host dendritic cells and T lymphocytes, thus preventing graft-versus-host disease and graft rejection, respectively. Sophisticated strategies of adoptive infusion of T-cell lines/clones specific for the most life-threatening pathogens (namely cytomegalovirus, Epstein-Barr virus, Aspergillus and Adenovirus) have been envisaged, and successfully tested in a few pilot trials, to protect the recipient in the early post-transplantation period. In these patients, also ex-vivo expanded mesenchymal stromal cells have been shown to be beneficial for preventing graft failure. Novel and effective strategies aimed at further augmenting the graft-versus-leukemia effect and at optimizing prevention/treatment of opportunistic/viral infections are warranted.
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Affiliation(s)
- Franco Locatelli
- Dipartimento di Ematologia ed Oncologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza S. Onofrio, Rome, Italy.
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42
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Alternative donors hematopoietic stem cells transplantation for adults with acute myeloid leukemia: Umbilical cord blood or haploidentical donors? Best Pract Res Clin Haematol 2011; 23:207-16. [PMID: 20837332 DOI: 10.1016/j.beha.2010.06.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Use of allogeneic transplantation for patients with acute myeloid leukemia (AML) depends mainly on the risk of the disease, and HLA matched donor availability. In patients with high-risk leukemia, in the absence of a HLA (human leukocyte antigen) matched donor, alternative donors such as unrelated umbilical cord blood (UCB) or haploidentical donor (haplo) have been currently used. Both strategies have important advantages such as shorter time to transplant, which is particularly relevant to patients requiring urgent transplantation, and tolerance of HLA mismatched graft that make possible that a donor can be found for virtually all patients. However, in spite of higher incidence of graft failure in UCB transplatation recipients and higher relapse incidence after haplo transplants, final outcomes seem to be comparable with HLA matched unrelated hematopoietic stem cell transplantation (bone marrow or peripheral blood). Therefore, the complexity of choosing the best alternative donor will depend on urgency of the transplantation, status and risk of the disease, donor criteria and center experience. Here we review the current status of UCBT and haplo transplants to treat adults with high-risk acute myeloid leukemia and we discuss the main issues associated with the use of both hematopoietic stem cell transplant approaches.
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van Walraven SM, Ball LM, Koopman HM, Switzer GE, Ropes-de Jong CMH, de Jong A, Bredius RGM, Egeler RM. Managing a dual role-experiences and coping strategies of parents donating haploidentical G-CSF mobilized peripheral blood stem cells to their children. Psychooncology 2010; 21:168-75. [DOI: 10.1002/pon.1885] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Revised: 10/18/2010] [Accepted: 10/18/2010] [Indexed: 11/09/2022]
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Kopp HG, Wirths S, Faul C, Bethge W, Scheding S, Brugger W, Kanz L, Vogel W. Long-term results after transplantation of CD34+ selected (CellPro) versus unselected peripheral blood progenitor cells (PBPC) from related allogeneic donors. J Cancer Res Clin Oncol 2010; 136:1921-7. [PMID: 20217128 DOI: 10.1007/s00432-010-0851-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Accepted: 02/17/2010] [Indexed: 11/25/2022]
Abstract
PURPOSE To determine the long-term outcome of patients after allogeneic transplantation of T-cell depleted versus unmanipulated hematopoietic stem cell grafts with respect to incidence of GvHD and overall survival in 50 consecutive patients. METHODS In this prospective phase II study utilizing biological randomization, 50 sibling donors were mobilized with G-CSF. Positive selection of CD34+ cells (Ceprate SC; CellPro, USA) was performed in good mobilizers (n = 25; group A), but not in poor mobilizers (n = 25; group B). Patients had hematological malignancies. Median patient age was 44 years (range, 19-57). Numbers of CD3+ cells were 0.5 ± 0.4 × 10(6)/kg in group A and 216 ± 127 × 10(6)/kg in group B. RESULTS Hematological recovery was rapid in both groups. Patients in group A had no grade III-IV acute GvHD, whereas 6 out of 22 evaluable patients in group B had grade III-IV acute GvHD with fatal outcome in four cases (P < 0.01). Similarly, the incidence of chronic GvHD was lower in patients in group A (35 vs. 65%). However, there was a higher relapse rate in group A (11/25) versus group B (4/25, P < 0.05). At a follow-up of 10 years after transplantation, eight (32%) and 10 patients (40%) were relapse-free and alive in groups A and B, respectively. CONCLUSIONS Risk factors for survival in a multivariate analysis were remission status prior to transplantation (CR vs. no CR), occurrence of acute and chronic GvHD, and relapse. The use of the CellPro device for CD34 positive selection per se did not have an influence on overall survival.
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Affiliation(s)
- Hans-Georg Kopp
- Department of Internal Medicine II, Division of Hematology and Oncology, Immunology, and Rheumatology, University of Tübingen, Tübingen, Germany
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Smiers FJ, Van de Vijver E, Delsing BJP, Lankester AC, Ball LM, Rings EHHM, van Rheenen PF, Bredius RGM. Delayed immune recovery following sequential orthotopic liver transplantation and haploidentical stem cell transplantation in erythropoietic protoporphyria. Pediatr Transplant 2010; 14:471-5. [PMID: 19735434 DOI: 10.1111/j.1399-3046.2009.01233.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
A nine-yr-old boy with EPP suffered from severe skin burns and liver failure caused by progressive cholestasis and fibrosis. OLT was performed without major complications. Four months following liver transplantation he underwent parental haploidentical HSCT. The myeloablative conditioning regimen was relatively well tolerated and hematological engraftment was rapid (on day 10). Protoporphyrin concentrations returned to normal following HSCT. However, immune recovery was significantly delayed. Varicella zoster virus reactivation resulted in impaired vision, prolonged hospitalization and eventually in multiorgan failure and death. Sequential liver and haploidentical HSCT proved feasible though a high risk procedure in this EPP patient. The management of post-IST after these combined transplantations remains a challenge and needs to be further established.
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Affiliation(s)
- Frans J Smiers
- Division of Immunology, Hematology, Oncology, Bone marrow transplantation and Auto-immune disease, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
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Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood 2010; 115:3437-46. [PMID: 20040760 DOI: 10.1182/blood-2009-03-207001] [Citation(s) in RCA: 141] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Abstract
T cell–depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) is an option to treat children with very high-risk acute lymphoblastic leukemia (ALL) lacking an HLA-identical donor. We analyzed 127 children with ALL who underwent haploHSCT in first (n = 22), second (n = 48), or third (n = 32), complete remission or in relapse (n = 25). The 5-year leukemia-free survival (LFS) was 30%, 34%, 22%, and 0%, respectively. A risk-factor analysis was performed for patients who underwent transplantation in remission (n = 102). Five-year nonrelapse mortality (NRM), relapse incidence (RI), and LFS were 37%, 36%, and 27%, respectively. A trend of improved LFS rate and decreased RI was observed for children given a graft with higher number of CD34+ cells (adjusted P = .09 and P = .07, respectively). In a multivariate analysis, haploHSCT performed in larger centers (performing ≥ 231 allotransplantations in the studied period) was associated with improved LFS rate and decreased RI (adjusted P = .01 and P = .04, respectively), adjusting for different patient-, disease-, and transplant-related factors such as number of previous autotransplantations, cytomegalovirus serology status, type of T-cell depletion, and use of total body irradiation and antithymocyte globulin. In conclusion, higher CD34+ cell dose and better patient selection may improve outcomes of children with ALL who undergo a haploHSCT. Transplant centers initiating programs on haploHSCT for children may collaborate with more experienced centers.
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Graft manipulation and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation from mismatched unrelated and mismatched/haploidentical related donors in pediatric leukemia patients. J Pediatr Hematol Oncol 2010; 32:e85-90. [PMID: 20216238 DOI: 10.1097/mph.0b013e3181cf813c] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Transplant-related problems have been partially overcome by using reduced-intensity conditioning (RIC), graft engineering, and alternative donors. In all, 21 leukemia patients with no suitable donor received a hematopoietic stem cell transplantation from a mismatched/haploidentical related (n=16) or unrelated donor (n=5). Fludarabine-RIC and PBSC graft were used. Manipulation was done by CD34+ selection (n=9) or CD3/CD19 depletion (n=12). Results were compared with patients (n=26) conditioned with the same regimen and grafted with a CD34+-selected PBSC from identical related donors. Median time to neutrophil recovery was 12 days (range, 10-19 d). Platelet engraftment was faster with a CD3/CD19-depleted graft (median, 11 d; range, 9-21) than with a CD34+ graft (median, 14 d; range, 9-53; P=0.003). Full donor chimerism in bone marrow CD34+ cells was higher in CD3/CD19-depleted graft group compared with CD34+-selected group (P=0.02). CD3/CD19 depletion showed higher natural killer cell counts even after 1 year. Nonrelapse mortality (7% for matched CD34+-selected grafts and 11% for mismatched/haplo-CD3/CD19-depleted grafts), relapse probability (27% for related CD34+-selected patients and 33% for related CD3/CD19-depleted patients), and disease-free survival were similar for both the groups. In conclusion, using graft engineering procedures after RIC for hematopoietic stem cell transplantation offers a high probability of engraftment, fast immune recovery, and very low mortality even with mismatched donors.
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48
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Abstract
Currently, it is possible to find a hematopoietic stem cell (HSC) donor for virtually all patients with acute leukemia who have an indication to receive an allogeneic hematopoietic stem cell transplant (HSCT) and lack a human leukocyte antigen (HLA)-identical sibling or a well-matched HLA unrelated donor (URD). According to the ethnicity of the patients and the donor registry, approximately 25% to 60% of patients will not find an 8/8 HLA-matched unrelated donor. Other alternative donors, such as HLA-mismatched related donor or unrelated donor umbilical cord blood (UCB), have emerged to solve the lack of a sibling or well-matched URD. In the haploidentical HSCT setting, new techniques of T-cell depletion, new approaches using combinations of immunosuppressive drugs or different conditioning regimens, and developments on immunotherapy have focused attention on this option. Therefore, any physician has to carefully evaluate, for each patient in need of an allograft, all of the possible alternatives in order to choose the best HSC donor, taking into account type of disease to be transplanted, urgency of transplantation, donor characteristics, and center experience. This review evaluates the current status of haploidentical HSCT in acute leukemia, its advantages and remaining limitations compared to other stem cell sources, and how these data may be used in the development of donor selection algorithms.
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Peters C, Cornish JM, Parikh SH, Kurtzberg J. Stem cell source and outcome after hematopoietic stem cell transplantation (HSCT) in children and adolescents with acute leukemia. Pediatr Clin North Am 2010; 57:27-46. [PMID: 20307710 DOI: 10.1016/j.pcl.2010.01.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation from siblings, unrelated donors or HLA mismatched family members has become an important procedure to offer a chance of cure to children and adolescents with acute leukemia at high risk of relapse and those with certain genetic diseases. Bone marrow (BM) was the only stem cell source for many years. During the past 15 years, peripheral blood stem cells from granulocyte colony-stimulating factor (G-CSF) mobilized healthy donors, or umbilical cord blood from related or unrelated donors, have become available. Each stem cell source has different risks/benefits for patients and donors, the choice depending not only on availability, but also on HLA compatibility and urgency of the HSCT. This review will analyze the advantages and limitations of each of these options, and the main criteria which can be applied when choosing the appropriate stem cell source for pediatric transplant recipients with acute leukemia.
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Affiliation(s)
- Christina Peters
- Stem Cell Transplantation Unit, St Anna Children's Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria.
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Abstract
Leukemia represents the most common pediatric malignancy, accounting for approximately 30% of all cancers in children less than 20 years of age. Most children diagnosed with leukemia are cured without hematopoietic stem cell transplantation (HSCT), but for some high-risk subgroups, allogeneic HSCT plays an important role in their therapeutic approach. The characteristics of these high-risk subgroups and the role of HSCT in childhood leukemias are discussed.
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Affiliation(s)
- Alan S. Wayne
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Building 10, Room 1-3750, 9000 Rockville Pike, MSC 1104, Bethesda, MD 20892-1104, Tel: 301-496-4256,
| | - Kristin Baird
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Building 10, Room 1-3750, 9000 Rockville Pike, MSC 1104, Bethesda, MD 20892-1104, Tel: 301-496-4256
| | - R. Maarten Egeler
- Department of Pediatrics/BMT Unit, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands, Tel: +31-71-526-2166,
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