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British Journal of Hospital Medicine... Jan 2019Haematopoietic stem cell transplantation was proposed as a treatment strategy just over 60 years ago. Owing to great advances in the field, haematopoietic stem cell... (Review)
Review
Haematopoietic stem cell transplantation was proposed as a treatment strategy just over 60 years ago. Owing to great advances in the field, haematopoietic stem cell transplantation has become an established method for the treatment of many haemato-oncological, immunological and hereditary conditions with the potential of cure. The number of haematopoietic stem cell transplants performed worldwide reached one million by 2012. This review provides an overview of autologous and allogeneic haematopoietic stem cell transplantation including disease indications, the individual steps of the procedure and outcome, and highlights achievements in the treatment of autoimmune diseases. Although autoimmune conditions account for only 1% of indications for autologous haematopoietic stem cell transplant, this is increasingly used to treat high-risk autoimmune diseases. Haematopoietic stem cell transplantation can induce long-term remission by resetting the immune system via eradication of autoreactive immune cells and the generation of a de novo self-tolerant immune system. Data seem most encouraging in multiple sclerosis and systemic sclerosis and it is likely that the number of procedures performed to treat these conditions will rise in the future.
Topics: Autoimmune Diseases; Crohn Disease; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Multiple Sclerosis; Scleroderma, Systemic; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous
PubMed: 30592675
DOI: 10.12968/hmed.2019.80.1.33 -
Blood Jul 2014An essential component of allogeneic and autologous hematopoietic cell transplantation (HCT) is the conditioning regimen administered before the hematopoietic cell... (Review)
Review
An essential component of allogeneic and autologous hematopoietic cell transplantation (HCT) is the conditioning regimen administered before the hematopoietic cell infusion. Early regimens relied on dose intensity, assuming that high-dose chemoradiotherapy would eliminate malignant disease and reinfusion of the graft would then restore hematopoiesis. However, as the contribution of graft-versus-tumor effects to the success of allogeneic HCT was recognized over time, in an effort to exploit these, many investigators lowered the dose of radiation and chemotherapeutic agents in the preparative regimen. This resulted in a major paradigm shift, and consequently, the pool of eligible patients underwent a remarkable expansion. In this article, we provide a review of the definition of high-dose, reduced-intensity, and nonmyeloablative conditioning regimens, the most commonly used agents and combinations, and the evolution of some early regimens. We also provide a brief review of the toxicities associated with these regimens.
Topics: Allografts; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Autografts; Clinical Trials as Topic; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Myeloablative Agonists; Radioimmunotherapy; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 24914142
DOI: 10.1182/blood-2014-02-514778 -
Frontiers in Immunology 2021Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse... (Review)
Review
Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.
Topics: Acute Disease; Adult; Disease-Free Survival; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Remission Induction; Transplantation Conditioning; Transplantation, Homologous
PubMed: 34012445
DOI: 10.3389/fimmu.2021.659595 -
Blood Advances Oct 2019Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens...
Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.
Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Clinical Decision-Making; Disease Management; Graft vs Host Disease; HLA Antigens; Histocompatibility Testing; Humans; Prognosis; Severity of Illness Index; Siblings; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Young Adult
PubMed: 31648332
DOI: 10.1182/bloodadvances.2019000722 -
Blood Reviews Jan 2020Solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are at increased risk for developing infections due to underlying... (Review)
Review
Solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are at increased risk for developing infections due to underlying immunosuppression. Antibiotic use, and in HSCT recipients, the use of preparative regimens prior to transplantation can deplete gut commensal bacteria, resulting in intestinal dysbiosis. Emerging evidence in transplant patients, particularly HSCT, suggest that disturbances in gut microbiota populations are associated with a number of adverse outcomes. Here, we review the outcomes of HSCT and SOT recipients with gut microbiota imbalance or dysbiosis, explore the nascent field of gut microbiome therapeutic approaches including fecal microbiota transplantation and the use of precision probiotics in HSCT and SOT recipients.
Topics: Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Hematopoietic Stem Cell Transplantation; Humans; Organ Transplantation; Transplantation Conditioning
PubMed: 31492463
DOI: 10.1016/j.blre.2019.100614 -
Current Opinion in Hematology Jul 2017Hematopoietic stem cells (HSCs) and progenitors are tasked with maintaining hematopoietic homeostasis in the face of numerous insults and challenges, including... (Review)
Review
PURPOSE OF REVIEW
Hematopoietic stem cells (HSCs) and progenitors are tasked with maintaining hematopoietic homeostasis in the face of numerous insults and challenges, including infection, inflammation, and exsanguination. HSCs possess the remarkable ability to reconstitute the entire hematopoietic system of an organism whose own hematopoietic system has been ablated. This ability is exploited routinely in the clinic via HSC transplantation (HSCT). Here, we focus on the physiological and molecular bottlenecks overcome by HSCs during transplantation.
RECENT FINDINGS
During transplantation, HSCs encounter a damaged bone marrow niche, characterized molecularly by increases in oxygen concentrations and an altered cytokine milieu. New mechanisms and pathways have been recently implicated during HSCT, including transplanted HSC-dependent secretion of conditioning molecules that facilitate engraftment and pathways that protect HSCs from perturbed organelle homeostasis.
SUMMARY
Better understanding the molecular processes HSCs employ to withstand the stress of transplant will illuminate novel targets for further improving conditioning regimens and engraftment during HSCT.
Topics: Animals; Cell Movement; Epigenesis, Genetic; Gene Expression Regulation; Graft Survival; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Homeostasis; Humans; Organelles; Oxidative Stress; Reactive Oxygen Species; Stem Cell Niche; Stress, Physiological; Transplantation Conditioning
PubMed: 28375987
DOI: 10.1097/MOH.0000000000000347 -
British Journal of Haematology Jan 2019Autologous stem cell transplantation is the standard salvage strategy for young and fit patients with Hodgkin lymphoma failing induction therapy, and is effective in... (Review)
Review
Autologous stem cell transplantation is the standard salvage strategy for young and fit patients with Hodgkin lymphoma failing induction therapy, and is effective in nearly 50% of cases. The quality of response at transplantation is the most relevant prognostic aspect, as patients in complete response can obtain better outcomes. Therefore, first-line salvage treatments applied before transplantation need to produce high quality responses without excessive myelotoxicity and without affecting peripheral blood stem cell mobilisation. In this sense, the incorporation of new agents active in Hodgkin lymphoma, such as brentuximab vedotin and anti-programmed death 1 antibodies, in conventional regimens, may help to enhance complete remission rates. Working on conditioning regimen and applying a post-autologous consolidation treatment (for example with brentuximab vedotin) are two ways for improving transplant outcomes, particularly in patients displaying high-risk features for early relapse or progression. Allogeneic transplantation maintains its curative potential also in the era of new drugs, although its most correct timing and the most suitable sequence of post-autologous salvage treatments still remain to be determined.
Topics: Brentuximab Vedotin; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Immunoconjugates; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous
PubMed: 30407612
DOI: 10.1111/bjh.15639 -
Hematology/oncology and Stem Cell... Dec 2017Allotransplantation cures patients by cytoreduction and the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse; both eliminate residual disease. The... (Review)
Review
Allotransplantation cures patients by cytoreduction and the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse; both eliminate residual disease. The spectrum of conditioning intensity influences toxicities and non-relapse mortality. The spectrum of tumor sensitivity to the GVL response influences relapse. Balancing tolerable toxicities (influenced by patients' performance status and comorbidities) is also influenced by the graft. Intense immunosuppression (for engraftment and graft-versus-host disease prevention) may constrain the immunologic potency of the graft and limit the antineoplastic capacity of the transplant, thus requiring more intense or more effective conditioning regimens to limit the risks of relapse and permit satisfactory disease-free survival.
Topics: Allografts; Graft Survival; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Neoplasms; Transplantation Conditioning
PubMed: 28641099
DOI: 10.1016/j.hemonc.2017.05.002 -
Frontiers in Immunology 2022
Topics: Transplantation Conditioning; Transplantation, Homologous
PubMed: 35812424
DOI: 10.3389/fimmu.2022.953185 -
Trends in Immunology Nov 2017Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field,... (Review)
Review
Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation (BMT) with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism such protocols can permit central deletional tolerance, but with a significant risk of graft-versus-host (GVH) disease (GVHD). By contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells (Tregs) followed by gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.
Topics: Animals; Bone Marrow Transplantation; Chimerism; Clonal Deletion; Humans; Kidney Transplantation; T-Lymphocytes, Regulatory; Transplantation Chimera; Transplantation Conditioning; Transplantation Immunology; Transplantation Tolerance
PubMed: 28826941
DOI: 10.1016/j.it.2017.07.008