In Vivo Emergence of UL56 C325Y Cytomegalovirus Resistance to Letermovir in a Patient with Acute Myeloid Leukemia after Hematopoietic Cell Transplantation

CMV associated tissue-invasive disease is associated with a considerable risk of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recently, the terminase inhibitor letermovir (LMV) has been approved for prophylaxis of CMV infection in HSCT. We hereby report a 60-year-old female experiencing CMV reactivation after HSCT in a CMV seronegative donor-constellation. Due to ongoing elevated CMV viral load and drug-associated myelosuppression, which prevented ganciclovir therapy, treatment was replaced by foscarnet. Due to nephrotoxicity, foscarnet was switched to LMV. The patient developed skin GvHD and prednisolone was started. Subsequently, CMV viremia worsened despite LMV therapy. Genotyping revealed the mutation C325Y of the CMV UL56 terminase being associated with high-level resistance against LMV. Prolonged uncontrolled low-level viremia due to prednisolone treatment may have favored the selection of drug-resistant CMV. Despite the excellent toxicity profile of LMV, physicians should be aware of risk factors for the emergence of resistance.

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High-Level in Vivo Gene Marking after Gene-Modified Autologous Hematopoietic Stem Cell Transplantation without Marrow Conditioning in Nonhuman Primates

Molecular Therapy ◽

10.1016/j.ymthe.2004.06.146 ◽

2004 ◽

Vol 10 (3) ◽

pp. 469-477 ◽

Cited By ~ 11

Author(s):

Kyoji Ueda ◽

Yutaka Hanazono ◽

Hiroaki Shibata ◽

Naohide Ageyama ◽

Yasuji Ueda ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Nonhuman Primates ◽

Hematopoietic Stem ◽

High Level

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Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Blood ◽

10.1182/blood-2004-08-3213 ◽

2005 ◽

Vol 105 (4) ◽

pp. 1828-1836 ◽

Cited By ~ 122

Author(s):

Alan M. Hanash ◽

Robert B. Levy

Keyword(s):

T Cells ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Disease Recurrence ◽

Hematopoietic Cell ◽

Allogeneic Bone ◽

Hematopoietic Stem

AbstractAllogeneic bone marrow transplantation (BMT) is a potentially curative treatment for both inherited and acquired diseases of the hematopoietic compartment; however, its wider use is limited by the frequent and severe outcome of graft-versus-host disease (GVHD). Unfortunately, efforts to reduce GVHD by removing donor T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic hematopoietic stem/progenitor cell engraftment without inducing GVHD could increase numbers of potential recipients while broadening the pool of acceptable donors. Although unfractionated CD4+ T cells have not been shown to be an efficient facilitating population, CD4+CD25+ regulatory cells (T-reg's) were examined for their capacity to support allogeneic hematopoietic engraftment. In a murine fully major histocompatibility complex (MHC)-mismatched BMT model, cotransplantation of donor B6 T-reg's into sublethally conditioned BALB/c recipients supported significantly greater lineage-committed and multipotential donor progenitors in recipient spleens 1 week after transplantation and significantly increased long-term multilineage donor chimerism. Donor engraftment occurred without GVHD-related weight loss or lethality and was associated with tolerance to donor and host antigens by in vitro and in vivo analyses. Donor CD4+CD25+ T cells may therefore represent a potential alternative to unfractionated T cells for promotion of allogeneic engraftment in clinical hematopoietic cell transplantation. (Blood. 2005;105:1828-1836)

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Mesenchymal stromal cells in hematopoietic cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2020002646 ◽

2020 ◽

Vol 4 (22) ◽

pp. 5877-5887

Author(s):

Andre J. Burnham ◽

Lisa P. Daley-Bauer ◽

Edwin M. Horwitz

Keyword(s):

Cell Transplantation ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Hematopoietic Cell Transplantation ◽

The United States ◽

Hematopoietic Cell ◽

Immunomodulatory Activity ◽

Critical Determinant ◽

Hematopoietic Stem

Abstract Mesenchymal stromal cells (MSCs) are widely recognized to possess potent immunomodulatory activity, as well as to stimulate repair and regeneration of diseased or damaged tissue. These fundamental properties suggest important applications in hematopoietic cell transplantation. Although the mechanisms of therapeutic activity in vivo are yet to be fully elucidated, MSCs seem to suppress lymphocytes by paracrine mechanisms, including secreted mediators and metabolic modulators. Most recently, host macrophage engulfment of apoptotic MSCs has emerged as an important contributor to the immune suppressive microenvironment. Although bone marrow–derived MSCs are the most commonly studied, the tissue source of MSCs may be a critical determinant of immunomodulatory function. The key application of MSC therapy in hematopoietic cell transplantation is to prevent or treat graft-versus-host disease (GVHD). The pathogenesis of GVHD reveals multiple potential targets. Moreover, the recently proposed concept of tissue tolerance suggests a new possible mechanism of MSC therapy for GVHD. Beyond GVHD, MSCs may facilitate hematopoietic stem cell engraftment, which could gain greater importance with increasing use of haploidentical transplantation. Despite many challenges and much doubt, commercial MSC products for pediatric steroid-refractory GVHD have been licensed in Japan, conditionally licensed in Canada and New Zealand, and have been recommended for approval by an FDA Advisory Committee in the United States. Here, we review key historical data in the context of the most salient recent findings to present the current state of MSCs as adjunct cell therapy in hematopoietic cell transplantation.

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Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation

Journal of Molecular Medicine ◽

10.1007/s00109-019-01869-8 ◽

2019 ◽

Vol 98 (2) ◽

pp. 233-243 ◽

Cited By ~ 1

Author(s):

Eva Zebedin-Brandl ◽

Madeleine Themanns ◽

Zahra Kazemi ◽

Shahrooz Nasrollahi-Shirazi ◽

Marion Mussbacher ◽

...

Keyword(s):

Cord Blood ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Concomitant Administration ◽

Hematopoietic Cell ◽

List Type ◽

Hematopoietic Stem ◽

Mutual Antagonism ◽

Synergism And Antagonism

Abstract The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. Key messages Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.

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Selection of HIV-1 for Resistance to Fourth Generation Protease Inhibitors Reveals Two Independent Pathways to High-Level Resistance

10.1101/837120 ◽

2019 ◽

Author(s):

Ean Spielvogel ◽

Sook-Kyung Lee ◽

Shuntai Zhou ◽

Gordon J. Lockbaum ◽

Mina Henes ◽

...

Keyword(s):

Protease Inhibitors ◽

Selective Pressure ◽

Viral Fitness ◽

Fourth Generation ◽

Genetic Barrier ◽

High Level ◽

Hiv 1 ◽

Level Resistance ◽

Selection Of

SummaryWell-designed viral protease inhibitors (PIs) potently inhibit replication as well as create a high genetic barrier for resistance. Through in vivo selective pressure, we have generated high-level resistance against ten HIV-1 PIs and their precursor, the FDA-approved drug darunavir (DRV), achieving 1,000-fold resistance over the starting EC50. The accumulation of mutations revealed two pathways to high-level resistance, resulting in protease variants with up to 14 mutations in and outside of the active site. The two pathways demonstrate the interplay between drug resistance and viral fitness. Replicate selections showed that one inhibitor could select for resistance through either pathway, although subtle changes in chemical structure of the inhibitors led to preferential use of one pathway over the other. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high-level of selective pressure that is attainable with these fourth-generation protease inhibitors, and the interplay between selection of mutations to confer resistance while maintaining viral fitness.

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Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation

Annals of Hematology ◽

10.1007/s00277-021-04568-y ◽

2021 ◽

Author(s):

Aleksandra Wysocka-Słowik ◽

Lidia Gil ◽

Zuzanna Ślebioda ◽

Agnieszka Kręgielczak ◽

Barbara Dorocka-Bobkowska

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Transplantation ◽

Oral Mucositis ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Conditioning Regimen ◽

World Health ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Acute Myeloid

AbstractThis study was designed to investigate the frequency and severity of oral mucositis in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups based on the conditioning regimen used before transplantation. The intensity of oral inflammatory lesions induced by chemotherapy (oral mucositis) was evaluated according to a 5-point scale recommended by World Health Organization. Oral mucosa was investigated in all patients before the transplantation and during two subsequent stages of the post-transplantation procedure in relation to the conditioning regimen used. Mucositis in the oral cavity was observed in the majority of patients (66%) in the first week after transplantation, whereas the largest percentage of patients suffering oral lesions (74%) occurred in the second week after transplantation. A significantly higher percentage of patients with mucositis was observed in the group which underwent myeloablation therapy (74% of MAC and 50% of RIC patients in the first week; 83% of MAC and 53% of RIC patients in the second examination).The severity of mucositis after transplantation was higher in the MAC patients compared to the RIC patients. The highest mean value of the mucositis index was recorded in the second week in the MAC group (1.59). In AML sufferers receiving allo-HSCT, oral mucositis is a significant complication of the transplantation. This condition is more frequent and more severe in patients after treatment with myeloablation therapy.

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Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on?

Current Oncology ◽

10.3390/curroncol28010089 ◽

2021 ◽

Vol 28 (1) ◽

pp. 903-917

Author(s):

Mitchell Sabloff ◽

Steven Tisseverasinghe ◽

Mustafa Ege Babadagli ◽

Rajiv Samant

Keyword(s):

Cell Transplantation ◽

Total Body Irradiation ◽

Hematopoietic Cell Transplantation ◽

Conditioning Regimen ◽

Late Toxicity ◽

Hepatic Function ◽

Vascular Supply ◽

Entire Body ◽

Hematopoietic Stem ◽

Total Body

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.

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