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Leo luznik

Kenneth R Cooke, Leo Luznik, Stefanie Sarantopoulos, Frances T Hakim, Madan Jagasia, Daniel H Fowler, Marcel R M van den Brink, John A Hansen, Robertson Parkman, David B Miklos, Paul J Martin, Sophie Paczesny, Georgia Vogelsang, Steven Pavletic, Jerome Ritz, Kirk R Schultz, Bruce R Blazar
Chronic graft-versus-host disease (GVHD) is the leading cause of late, non-relapse, mortality and disability in allogeneic hematopoietic cell transplantation (HCT) patients and a major obstacle to improving outcomes. Chronic GVHD biology remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: • Summarize the current "state-of-the-science" regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps...
October 3, 2016: Biology of Blood and Marrow Transplantation
Tara M Robinson, Leo Luznik
No abstract text is available yet for this article.
September 13, 2016: Biology of Blood and Marrow Transplantation
Cameron McDonald-Hyman, Ryan Flynn, Angela Panoskaltsis-Mortari, Nicholas Peterson, Kelli P A MacDonald, Geoffrey R Hill, Leo Luznik, Jonathan S Serody, William J Murphy, Ivan Maillard, David H Munn, Laurence A Turka, John Koreth, Corey S Cutler, Robert J Soiffer, Joseph H Antin, Jerome Ritz, Bruce R Blazar
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions...
August 18, 2016: Blood
Christopher G Kanakry, David G Coffey, Andrea M H Towlerton, Ante Vulic, Barry E Storer, Jeffrey Chou, Cecilia C S Yeung, Christopher D Gocke, Harlan S Robins, Paul V O'Donnell, Leo Luznik, Edus H Warren
Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (n = 74) and antigen receptor sequencing (n = 35) in recipients of myeloablative, HLA-matched allogeneic BM transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower T cell receptor β (TRB) repertoire diversity than input donor repertoires. Recovering B cells were predominantly naive with immunoglobulin heavy chain locus (IGH) repertoire diversity similar to donors...
2016: JCI Insight
Ying-Jun Chang, Leo Luznik, Ephraim J Fuchs, Xiao-Jun Huang
In haploidentical stem cell transplantations (haplo-SCT), nearly all patients have more than one donor. A key issue in the haplo-SCT setting is the search for the best donor, because donor selection can significantly impact the incidences of acute and chronic graft-versus-host disease, transplant-related mortality, and relapse, in addition to overall survival. In this review, we focused on factors associated with transplant outcomes following unmanipulated haplo-SCT with anti-thymocyte globulin (ATG) or after T-cell-replete haplo-SCT with post-transplantation cyclophosphamide (PT/Cy)...
2016: Journal of Hematology & Oncology
Tara M Robinson, Paul V O'Donnell, Ephraim J Fuchs, Leo Luznik
Allogeneic blood or bone marrow transplantation (BMT) is a potentially curative therapy for high-risk hematologic malignancies not curable by standard chemotherapy, but the procedure is limited by the availability of human leukocyte antigen-matched donors for many patients, as well as toxicities including graft-versus-host disease (GVHD). Our group has developed the use of high-dose post-transplantation cyclophosphamide (PTCy) to selectively remove alloreactive T cells without compromising engraftment. This protocol has allowed for successful transplantation of human leukocyte antigen (HLA)-haploidentical (haplo) grafts, thus expanding the donor pool for the many patients who would not otherwise be a candidate for this life-saving procedure...
April 2016: Seminars in Hematology
Ryan Flynn, Katelyn Paz, Jing Du, Dawn K Reichenbach, Patricia A Taylor, Angela Panoskaltsis-Mortari, Ante Vulic, Leo Luznik, Kelli K P MacDonald, Geoffrey R Hill, Melanie S Nyuydzefe, Jonathan M Weiss, Wei Chen, Alissa Trzeciak, Jon S Serody, Ethan G Aguilar, William J Murphy, Ivan Maillard, David Munn, John Koreth, Corey S Cutler, Joseph H Antin, Jerome Ritz, Samuel D Waksal, Alexandra Zanin-Zhorov, Bruce R Blazar
Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic bone marrow transplantation (BMT). The discovery of novel therapeutics is dependent on assessment in preclinical murine models of cGVHD. Rho-associated kinase 2 (ROCK2) recently was shown to be implicated in regulation of interleukin-21 (IL-21) and IL-17 secretion in mice and humans. Here, we report that the selective ROCK2 inhibitor KD025 effectively ameliorates cGVHD in multiple models: a full major histocompatibility complex (MHC) mismatch model of multiorgan system cGVHD with bronchiolitis obliterans syndrome and a minor MHC mismatch model of sclerodermatous GVHD...
April 28, 2016: Blood
Jennifer A Kanakry, Leo Luznik
No abstract text is available yet for this article.
February 18, 2016: Blood
Monzr M Al Malki, Mary Horowitz, Rupert Handgretinger, Wing Leung, Denis-Claude Roy, Xiao-Jun Huang, Ephraim Fuchs, Franco Locatelli, Didier Blaise, Shin Mineishi, Massimo Martelli, Jeffrey Miller, Carl June, Hui-Sheng Ai, Leo Luznik, Domenico Mavilio, Enrico Lugli, Marcel R M van den Brink, Richard E Champlin, Stefan O Ciurea
Significant progress has been made over the past decade in haploidentical transplantation, with the development of novel methods to control intense alloreactive reactions generated in the major HLA-mismatched setting. Application of post-transplantation cyclophosphamide has gained worldwide acceptance as an effective and low-cost way to perform this type of transplantation, with outcomes now similar to those from HLA-matched unrelated donors. These advances have resulted in improved treatment-related mortality, whereas disease relapse has emerged as the most common cause of treatment failure...
April 2016: Biology of Blood and Marrow Transplantation
Johnnie J Orozco, Aimee Kenoyer, Ethan R Balkin, Ted A Gooley, Donald K Hamlin, D Scott Wilbur, Mark D Hylarides, Sofia H L Frost, Raya Mawad, Paul O'Donnell, Brenda M Sandmaier, Ephraim J Fuchs, Leo Luznik, Damian J Green, Ajay K Gopal, Oliver W Press, John M Pagel
Many patients with hematologic malignancies cannot tolerate hematopoietic cell transplantation (HCT), whereas others may not have a compatible human leukocyte antigen-matched donor. To overcome these limitations, we optimized a conditioning regimen employing anti-CD45 radioimmunotherapy (RIT) replacing total body irradiation (TBI) before haploidentical HCT in a murine model. Mice received 200 to 400 μCi (90)Y-anti-CD45 antibody (30F11), with or without fludarabine (5 days starting day -8), with cyclophosphamide (CY; days -2 and +2) for graft-versus-host disease prophylaxis, and 1...
January 21, 2016: Blood
Elad Jacoby, Allen Chen, David M Loeb, Christopher J Gamper, Elias Zambidis, Nicolas J Llosa, Jeffrey Huo, Kenneth R Cooke, Rick Jones, Ephraim Fuchs, Leo Luznik, Heather J Symons
High-dose cyclophosphamide given after HLA-matched related and unrelated allogeneic bone marrow transplantation (BMT) for patients with hematologic malignancies is effective single-agent graft-versus-host disease (GVHD) prophylaxis in adults. Data describing outcomes for pediatric and young adult patients have not been reported. Between the years 2007 and 2013, 29 pediatric and young adult patients ages ≤21 years of age treated at our institution for high-risk hematologic malignancies underwent myeloablative HLA-matched related T cell-replete BMT...
January 2016: Biology of Blood and Marrow Transplantation
Christopher G Kanakry, Ephraim J Fuchs, Leo Luznik
Allogeneic blood or bone-marrow transplantation (alloBMT) is a potentially curative treatment for a variety of haematological malignancies and nonmalignant diseases. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with alloBMT using other donors. Although only approximately one-third of patients have an HLA-matched sibling, nearly all patients have HLA-haploidentical related donors. Early studies using HLA-haploidentical alloBMT resulted in unacceptably high rates of graft rejection and graft-versus-host disease (GVHD), leading to high nonrelapse mortality and consequently poor survival...
January 2016: Nature Reviews. Clinical Oncology
Lindsey R Lombardi, Christopher G Kanakry, Marianna Zahurak, Nadira Durakovic, Javier Bolaños-Meade, Yvette L Kasamon, Douglas E Gladstone, William Matsui, Ivan Borrello, Carol Ann Huff, Lode J Swinnen, Robert A Brodsky, Richard F Ambinder, Ephraim J Fuchs, Gary L Rosner, Richard J Jones, Leo Luznik
Busulfan (Bu)/cyclophosphamide (Cy) is a standard conditioning platform for allogeneic transplantation. We developed a strategy separating the Cy into two pre/post-transplantation doses (PTCy), providing myeloablative conditioning and single-agent graft-versus-host disease (GVHD) prophylaxis. We investigated the impact of Bu route on treatment-related toxicity for 131 consecutive adult patients. Busulfan was administered in four daily divided doses either orally (n = 72) or intravenously (n = 59) with pharmacokinetics on the first-dose and as necessary on subsequent doses to achieve a target area-under-the-concentration-curve (AUC) of 800-1400 μmol*min/L per dose...
2016: Leukemia & Lymphoma
Yvette L Kasamon, Javier Bolaños-Meade, Gabrielle T Prince, Hua-Ling Tsai, Shannon R McCurdy, Jennifer A Kanakry, Gary L Rosner, Robert A Brodsky, Karlo Perica, B Douglas Smith, Douglas E Gladstone, Lode J Swinnen, Margaret M Showel, William H Matsui, Carol Ann Huff, Ivan Borrello, Keith W Pratz, Michael A McDevitt, Ivana Gojo, Amy E Dezern, Satish Shanbhag, Mark J Levis, Leo Luznik, Richard F Ambinder, Ephraim J Fuchs, Richard J Jones
PURPOSE: Recent advances in nonmyeloablative (NMA), related HLA-haploidentical blood or marrow transplantation (haplo-BMT) have expanded the donor pool. This study evaluated the effect of age on NMA haplo-BMT outcomes in patients age 50 to 75 years. PATIENTS AND METHODS: A retrospective analysis was performed of 271 consecutive patients with hematologic malignancies, age 50 to 75 years, who received NMA, T-cell-replete haplo-BMT with high-dose post-transplantation cyclophosphamide...
October 1, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Jennifer A Kanakry, Christopher D Gocke, Javier Bolaños-Meade, Douglas E Gladstone, Lode J Swinnen, Amanda L Blackford, Ephraim J Fuchs, Carol Ann Huff, Ivan Borrello, William H Matsui, Robert A Brodsky, Gary L Rosner, Satish Shanbhag, Leo Luznik, Richard J Jones, Richard F Ambinder, Yvette L Kasamon
Outcomes of nonmyeloablative (NMA), HLA-haploidentical (haplo), related-donor allogeneic blood or marrow transplantation (allo-BMT) with high-dose post-transplantation cyclophosphamide (PTCy) appear to be similar to those using HLA-matched donors. Thus, it may be possible to prioritize donor factors other than HLA matching that could enhance antitumor activity. The Fc receptor polymorphism FCGR3A-158VV may confer greater sensitivity to rituximab than FCGR3A-158FF. In a prospective phase II study of NMA, related-donor allo-BMT with PTCy and post-transplantation rituximab for patients with B cell lymphomas, we hypothesized that donor selection that prioritized FCGR3A-158 polymorphism over HLA matching would be feasible, safe, and improve outcomes...
December 2015: Biology of Blood and Marrow Transplantation
Stefan O Ciurea, Mei-Jie Zhang, Andrea A Bacigalupo, Asad Bashey, Frederick R Appelbaum, Omar S Aljitawi, Philippe Armand, Joseph H Antin, Junfang Chen, Steven M Devine, Daniel H Fowler, Leo Luznik, Ryotaro Nakamura, Paul V O'Donnell, Miguel-Angel Perales, Sai Ravi Pingali, David L Porter, Marcie R Riches, Olle T H Ringdén, Vanderson Rocha, Ravi Vij, Daniel J Weisdorf, Richard E Champlin, Mary M Horowitz, Ephraim J Fuchs, Mary Eapen
We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens...
August 20, 2015: Blood
Christopher G Kanakry, Marcos J de Lima, Leo Luznik
Allogeneic hematopoietic cell transplantation (alloHCT) provides a potentially curative therapy for patients with high-risk or chemorefractory acute myeloid leukemia (AML). Historically, the applicability of alloHCT has been limited as only 30%-35% of patients have human leukocyte antigen (HLA)-matched siblings and outcomes using other donor types have been markedly inferior due to excess toxicity, graft failure, graft-versus-host disease (GVHD), and consequently non-relapse mortality. Advances in HLA typing, GVHD prophylactic approaches, and other transplantation techniques have successfully addressed these historical challenges...
July 2015: Seminars in Hematology
Kimberly A Noonan, Carol A Huff, Janice Davis, M Victor Lemas, Susan Fiorino, Jeffrey Bitzan, Anna Ferguson, Amy Emerling, Leo Luznik, William Matsui, Jonathan Powell, Ephraim Fuchs, Gary L Rosner, Caroline Epstein, Lakshmi Rudraraju, Richard F Ambinder, Richard J Jones, Drew Pardoll, Ivan Borrello
Successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time. We hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. We describe the results from the first clinical trial using MILs in MM. Twenty-five patients with either newly diagnosed or relapsed disease had their MILs harvested, activated and expanded, and subsequently infused on the third day after myeloablative therapy...
May 20, 2015: Science Translational Medicine
Hanna A Knaus, Christopher G Kanakry, Leo Luznik, Ivana Gojo
Intrinsic immune responses to acute leukemia are inhibited by a variety of mechanisms, such as aberrant antigen expression by leukemia cells, secretion of immunosuppressive cytokines and expression of inhibitory enzymes in the tumor microenvironment, expansion of immunoregulatory cells, and activation of immune checkpoint pathways, all leading to T cell dysfunction and/or exhaustion. Leukemic cells, similar to other tumor cells, hijack these inhibitory pathways to evade immune recognition and destruction by cytotoxic T lymphocytes...
May 17, 2015: Current Drug Targets
Christopher G Kanakry, Sudipto Ganguly, Leo Luznik
In two recent publications, we demonstrated that after allogeneic stimulation, regulatory T cells (Tregs) increase expression of aldehyde dehydrogenase (ALDH), the major in vivo mechanism of cyclophosphamide detoxification, thereby becoming cyclophosphamide resistant. Differential ALDH expression may explain why cyclophosphamide has pro- and anti-inflammatory effects that are temporally and contextually dependent.
March 2015: Oncoimmunology
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