Graft-versus-host disease prophylaxis: Pathophysiology-based review on current approaches and future directions

Martínez-Cibrián, Núria; Zeiser, Robert; Pérez-Simón, José A.

doi:10.1016/j.blre.2020.100792

Cited by 58 publications

(39 citation statements)

References 109 publications

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“…In contrast to transplant rejection, which is mediated by the host immune response, graft-versus-host disease (GvHD) is caused by donor immunocompetent T cells primed by either donor or host APCs inducing an immune response against the host. The pathophysiology of GvHD can be acute or chronic depending on timing and range of symptoms [ 74 ].…”

Section: Application For Car Treg Therapymentioning

confidence: 99%

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

2022

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Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in initial clinical findings. To address this limitation, antigen specificity can be conferred to Tregs by engineering the expression of transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR). In contrast to TCR Tregs, CAR Tregs are major histocompatibility complex (MHC) independent and less dependent on interleukin-2 (IL-2). Furthermore, CAR Tregs maintain Treg phenotype and function, home to the target tissue and show enhanced suppressive efficacy compared to polyclonal Tregs. Additional development of engineered CAR Tregs is needed to increase Tregs’ suppressive function and stability, prevent CAR Treg exhaustion, and assess their safety profile. Further understanding of Tregs therapeutic potential will be necessary before moving to broader clinical applications. Here, we summarize recent studies utilizing CAR Tregs in modulating immune responses in autoimmune diseases, transplantation, and gene therapy and future clinical applications.

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Section: Application For Car Treg Therapymentioning

confidence: 99%

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

2022

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“…The effects of ATRA on immunocompetent cells will be of particular importance in allotransplant recipients because immune-mediated antileukemic activity contributes to the overall antileukemic effect of this strategy but especially because immune-mediated complications contribute to the posttransplant non-relapse mortality [ 104 ]. ATRA is important for trafficking of immunocompetent cells, including the homing of various immune cell subsets to the gut that is one of the organs commonly affected in both acute and chronic graft versus host disease (GVHD) [ 105 , 106 ].…”

Section: Experimental and Clinical Studies Of Atra In Non-apl Variants Of Amlmentioning

confidence: 99%

Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

et al. 2021

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Even though allogeneic stem cell transplantation is the most intensive treatment for acute myeloid leukemia (AML), chemo-resistant leukemia relapse is still one of the most common causes of death for these patients, as is transplant-related mortality, i.e., graft versus host disease, infections, and organ damage. These relapse patients are not always candidates for additional intensive therapy or re-transplantation, and many of them have decreased quality of life and shortened expected survival. The efficiency of azacitidine for treatment of posttransplant AML relapse has been documented in several clinical trials. Valproic acid is an antiepileptic fatty acid that exerts antileukemic activity through histone deacetylase inhibition. The combination of valproic acid and all-trans retinoic acid (ATRA) is well tolerated even by unfit or elderly AML patients, and low-toxicity chemotherapy (e.g., azacitidine) can be added to this combination. The triple combination of azacitidine, valproic acid, and ATRA may therefore represent a low-intensity and low-toxicity alternative for these patients. In the present review, we review and discuss the general experience with valproic acid/ATRA in AML therapy and we discuss its possible use in low-intensity/toxicity treatment of post-allotransplant AML relapse. Our discussion is further illustrated by four case reports where combined treatments with sequential azacitidine/hydroxyurea, valproic acid, and ATRA were used.

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“…HSCT is a procedure that restores stem cells that have been destroyed by a preparative regimen including chemotherapy with or without total body irradiation delivered before stem cell infusion to optimize tumor cell kill and, in the case of allogeneic HSCT, immunosuppress the recipient to prevent graft rejection (Gagelmann and Kröger, 2021). In addition, allogeneic HSCT recipients receive immunosuppressive agents, namely, calcineurin inhibitors, for a prolonged period of time after transplant to mitigate the graft-versus-host reaction (Zeiser and Blazar, 2017;Martinez-Cibrian et al, 2020). According to these considerations, patients undergoing HSCT are at elevated risk for severe life-threatening infections (Sahin et al, 2016;Neofytos, 2019).…”

Section: Introductionmentioning

confidence: 99%

Management of Invasive Fungal Infections in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: The Turin Experience

Busca

Cinatti

Gill

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundAllogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are exposed to an increased risk of invasive fungal infections (IFIs) due to neutropenia, immunosuppressive treatments, graft-versus-host disease (GvHD) and incomplete immune reconstitution. Although clinical benefit from antifungal prophylaxis has been demonstrated, IFIs remain a leading cause of morbidity and mortality in these patients. In the last decades, attention has also been focused on potential risk factors for IFI to tailor an antifungal prevention strategy based on risk stratification.Aim of the StudyThis retrospective single-center study aimed to assess the epidemiology and the prognostic factors of IFI in a large cohort of allo-HSCT patients.MethodsBetween January 2004 and December 2020, 563 patients with hematological malignancies received an allo-HSCT at the Stem Cell Transplant Unit in Turin: 191 patients (34%) received grafts from a matched sibling donor, 284 (50.5%) from a matched unrelated donor, and 87 (15.5%) from an haploidentical family member. The graft source was peripheral blood in 81.5% of the patients. Our policy for antifungal prophylaxis included fluconazole in matched related and unrelated donors, while micafungin was administered in patients receiving haploidentical transplant. According to this practice, fluconazole was administered in 441 patients (79.6%) and micafungin in 62 (11.2%), while only 9 patients received mold-active prophylaxis. Galactomannan testing was routinely performed twice a week; patients with persisting fever unresponsive to broad spectrum antibiotics were evaluated with lung high-resolution computed tomography (HRCT) scan. In case of imaging suggestive of IFI, bronchoalveolar lavage (BAL) was performed whenever feasible.Statistical AnalysisOnly probable/proven IFI (PP-IFI) occurring during the first 12 months after transplant have been evaluated. IFIs were classified as probable or proven according to the new revised European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) consensus criteria. Multivariate competing risk regression, binary logistic, and proportional hazard models were performed to identify risk factors for PP-IFI.ResultsA total of 58 PP-IFIs (n = 47 probable; n = 11 proven) occurred in our patients resulting in a cumulative incidence of 4.1%, 8.1%, and 9.6% at 30, 180, and 365 days, respectively. Molds were the predominant agents (n = 50 Aspergillus; n = 1 Mucor), followed by invasive candidemia (n = 5 non-albicans Candida; n = 1 Candida albicans; n = 1 Trichosporon). Lung was the most frequent site involved in patients with mold infections (47/51, 92.2%). Median time from HSCT to IFI was 98.44 days (0–365 days). Only 34.5% of patients with IFI were neutropenic at the time of infection. The presence of IFI had a significant impact on overall survival at 1 year (IFI, 32.8% vs. non-IFI, 54.6%; p < 0.001). IFI-related mortality rate was 20.7% in the overall population, 17% in patients with probable IFI, and 36% in patients with proven IFI. Multivariate competing risk regression revealed that donor type was the factor significantly associated to the risk of IFI [subdistribution hazard ratio (SDHR), 1.91, IC 1.13–3.20; p = 0.015]. BAL was informative in a consistent number of cases (36/57, 63.2%) leading to the identification of fungal (21), bacterial (4), viral (3), and polymicrobial (8) infections. Overall, 79 patients (14%) received a diagnostic-driven treatment, and 63 patients (11.2%) received a fever-driven treatment. Liposomal amphoteric B was the drug used in the majority of patients receiving diagnostic-driven therapy (30/79, 38%), while caspofungin was administered more frequently in patients who received a fever-driven strategy (27/63, 42.9%).ConclusionAccording to our experience, a non-mold active prophylaxis in patients undergoing allo-HSCT is feasible when combined with an intensive diagnostic work-up including CT scan and BAL. BAL performed at the onset of the disease may provide informative results in most patients. A diagnostic-driven treatment strategy may contribute to limit the use of costly antifungal therapies.

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Graft-versus-host disease prophylaxis: Pathophysiology-based review on current approaches and future directions

Cited by 58 publications

References 109 publications

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

Management of Invasive Fungal Infections in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: The Turin Experience

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