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      A Prognostic Model Predicting Autologous Transplantation Outcomes in Children, Adolescents and Young Adults with Hodgkin Lymphoma

      research-article
      , MBBS, MD 1 , , PhD 2 , 3 , , MPH 2 , , MD 4 , , MD 5 , , MD 6 , , MD, PhD 7 , , MD, MS 8 , , MD, PhD 9 , , MD 10 , , MD, MS 11 , , MD 12 , , MD, FACP 13 , , MD, PhD, DSc(hon), FACP 14 , , MD, PhD 15 , , MD, PhD 16 , , MD 17 , , MD 18 , , MD 19 , , MD 20 , , MD 21 , , MD 22 , , MD, PhD 23 , , MD 21 , , MD, PhD 24 , 25 , , BHB, MBChB, FRACP, FRCPA 26 , , MD 27 , , MD 28 , , MD 29 , , MD, MPH 30 , , MD 31 , , MD, PhD 32 , , MD 33 , , MD, PhD 34 , , MD, PhD 35 , 36 , , MD 2
      Bone marrow transplantation
      CAYA, Autologous transplantation, Hodgkin lymphoma

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          Abstract

          Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pre-transplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995–2010. The probabilities of progression free survival (PFS) at 1, 5 and 10 years were 66% (95% CI: 62–70), 52% (95% CI: 48–57) and 47% (95% CI: 42–51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ≥90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low, intermediate and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64–80), 53% (95% CI: 47–59) and 23% (95% CI: 9–36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk for progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

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          Most cited references33

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          Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.

          A topic that has received attention in both the statistical and medical literature is the estimation of the probability of failure for endpoints that are subject to competing risks. Despite this, it is not uncommon to see the complement of the Kaplan-Meier estimate used in this setting and interpreted as the probability of failure. If one desires an estimate that can be interpreted in this way, however, the cumulative incidence estimate is the appropriate tool to use in such situations. We believe the more commonly seen representations of the Kaplan-Meier estimate and the cumulative incidence estimate do not lend themselves to easy explanation and understanding of this interpretation. We present, therefore, a representation of each estimate in a manner not ordinarily seen, each representation utilizing the concept of censored observations being 'redistributed to the right.' We feel these allow a more intuitive understanding of each estimate and therefore an appreciation of why the Kaplan-Meier method is inappropriate for estimation purposes in the presence of competing risks, while the cumulative incidence estimate is appropriate.
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            A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease.

            Two thirds of patients with advanced Hodgkin's disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail. Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkin's disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation. The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkin's disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.
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              Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.

              Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33). These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.
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                Author and article information

                Journal
                8702459
                2334
                Bone Marrow Transplant
                Bone Marrow Transplant.
                Bone marrow transplantation
                0268-3369
                1476-5365
                3 July 2015
                03 August 2015
                November 2015
                01 May 2016
                : 50
                : 11
                : 1416-1423
                Affiliations
                [1 ]Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Columbia University Medical Center, New York, NY
                [2 ]CIBMTR ® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI
                [3 ]Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI
                [4 ]Division of Hematology, Oncology and Blood & Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA
                [5 ]Pediatric Hematology/Oncology and Stem Cell Transplantation, New York Medical College, New York, NY
                [6 ]Division of Oncology, Washington University School of Medicine, St. Louis, MO
                [7 ]Oregon Health and Science University, Portland, OR
                [8 ]Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
                [9 ]Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
                [10 ]Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
                [11 ]Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI
                [12 ]South Texas Veterans Health Care System and University of Texas Health Science Center San Antonio, San Antonio, TX
                [13 ]Blood and Marrow Transplantation, Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, KS
                [14 ]Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom
                [15 ]Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC
                [16 ]Department of Haematology, Prince of Wales Hospital, Randwick NSW, Australia
                [17 ]Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO
                [18 ]Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX
                [19 ]Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, Morgantown, WV
                [20 ]Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada
                [21 ]Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
                [22 ]Seidman Cancer Center, University Hospitals Case Medical Center, Cleveland, OH
                [23 ]Pediatric Bone Marrow Transplant, University Hospitals Bristol NHS Trust, Bristol, United Kingdom
                [24 ]Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
                [25 ]Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden
                [26 ]Blood and Cancer Centre, Starship Children’s Hospital, Auckland, New Zealand
                [27 ]Bone Marrow Transplante Unit, FUNDALEU, Buenos Aires, Argentina
                [28 ]Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
                [29 ]Department of Internal Medicine, The Nebraska Medical Center, Omaha, NE
                [30 ]Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC
                [31 ]Division of Hematology, Mayo Clinic, Rochester, MN
                [32 ]Bone and Marrow Transplant Program, University of Minnesota Medical Center, Minneapolis, MN
                [33 ]Section of Hematology/Oncology, The University of Chicago, Chicago, IL
                [34 ]Fred Hutchinson Cancer Research Center, Seattle, WA
                [35 ]Servei d’Hematologia, Institut Català d’Oncologia, Hospital Duran i Reynals, Barcelona, Spain
                [36 ]Secretary, European Group for Blood and Marrow Transplantation
                Author notes
                Corresponding author: Mehdi Hamadani, MD, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226, USA; Phone: 414-805-0643; Fax: 414-805-0714; mhamadani@ 123456mcw.edu
                Article
                NIHMS703717
                10.1038/bmt.2015.177
                4633349
                26237164
                4bb25083-a288-4b92-927e-3aa2c87b8da0

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                History
                Categories
                Article

                Transplantation
                caya,autologous transplantation,hodgkin lymphoma
                Transplantation
                caya, autologous transplantation, hodgkin lymphoma

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