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1.
Cancer Med ; 12(7): 8228-8237, 2023 04.
Article in English | MEDLINE | ID: mdl-36653918

ABSTRACT

BACKGROUND: Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time-trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo-HCT) at our center from 2001-2017. METHODS: The patients were divided into two distinct treatment cohorts: era1 (2001-2010), and era2 (2011-2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD). RESULTS: Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4-year OS (34% vs. 83%, p < 0.001) and 4-year PFS (28% vs. 62%, p = 0.001) were significantly inferior in era1 compared to era2. The incidence of 1-year NRM was lower in era2 compared to era1 (5% vs. 34%, p = 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p = 0.50), but the incidence of chronic GVHD at 1 year was higher in era2 compared to era1 (55% vs. 21%, p = 0.03). CONCLUSIONS: Despite the advent of novel therapies, allo-HCT remains an important therapeutic option for patients with R/R HL.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Hodgkin Disease , Humans , Hodgkin Disease/drug therapy , Brentuximab Vedotin/therapeutic use , Neoplasm Recurrence, Local , Hematopoietic Stem Cell Transplantation/adverse effects , Chronic Disease , Graft vs Host Disease/etiology , Transplantation Conditioning , Retrospective Studies
2.
Bone Marrow Transplant ; 56(3): 544-551, 2021 03.
Article in English | MEDLINE | ID: mdl-33130819

ABSTRACT

The purpose of this review is to provide a framework for the cardiovascular evaluation and management of patients undergoing hematopoietic cell transplantation (HCT). To accomplish this, we have performed an extensive literature review, critically analyzed the available evidence, and developed a set of recommendations to guide best practice. Herein, we discuss the cardiovascular risk profile of patients undergoing HCT along with putative mechanisms of HCT-induced cardiovascular injury. We then present an algorithm for cardiovascular testing and risk mitigation of potential recipients. Last, we address the management of the most prevalent cardiovascular conditions associated with HCT recipients.


Subject(s)
Cardiovascular Diseases , Hematopoietic Stem Cell Transplantation , Cardiovascular Diseases/etiology , Heart Disease Risk Factors , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Risk Assessment , Risk Factors
3.
Exp Biol Med (Maywood) ; 245(17): 1543-1551, 2020 11.
Article in English | MEDLINE | ID: mdl-32762265

ABSTRACT

IMPACT STATEMENT: Aging is associated with DNA methylation (DNAm) changes. Recent advancement of the whole-genome DNAm analysis technology allowed scientists to develop DNAm-based age estimators. A majority of these estimators use DNAm data from a single tissue type such as blood. In 2013, a multi-tissue age estimator using DNAm pattern of 353 CpGs was developed by Steve Horvath. This estimator was named "epigenetic clock", and the improved version using DNAm pattern of 391 CpGs was developed in 2018. The estimated age by epigenetic clock is named DNAmAge. DNAmAge can be used as a biomarker of aging predicting the risk of age-associated diseases and mortality. Although the DNAm-based age estimators were developed, the mechanism of epigenetic aging is still enigmatic. The biological significance of epigenetic aging is not well understood, either. This minireview discusses the current understanding of the mechanism of epigenetic aging and the future direction of aging research.


Subject(s)
Aging/genetics , Epigenesis, Genetic , Animals , Biological Clocks/genetics , Cell Hypoxia/genetics , DNA Methylation/genetics , Hematopoietic Stem Cells/metabolism , Humans
4.
Biol Blood Marrow Transplant ; 23(7): 1117-1121, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28396160

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Survival Analysis , Young Adult
5.
Nat Commun ; 7: 11154, 2016 Apr 04.
Article in English | MEDLINE | ID: mdl-27040177

ABSTRACT

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3ß) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy.


Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Killer Cells, Natural/immunology , Leukemia, Myeloid, Acute/immunology , Aminophenols/chemistry , Aminophenols/pharmacology , Animals , Cellular Microenvironment , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Immunotherapy , Intercellular Adhesion Molecule-1/metabolism , Maleimides/chemistry , Maleimides/pharmacology , Mice , NF-kappa B/metabolism , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Tumor Necrosis Factor-alpha
6.
Biol Blood Marrow Transplant ; 16(11): 1467-503, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20699125

ABSTRACT

Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Neoplasm Recurrence, Local/therapy , Hodgkin Disease/therapy , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukemia, Myeloid, Acute/therapy , Lymphocyte Transfusion , Lymphoma, Non-Hodgkin , Multiple Myeloma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Recurrence , Transplantation, Homologous , Treatment Failure
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