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Orly R Klein, Jessica Buddenbaum, Noah Tucker, Allen R Chen, Christopher J Gamper, David Loeb, Elias Zambidis, Nicolas J Llosa, Jeffrey S Huo, Nancy Robey, Mary Jo Holuba, Yvette L Kasamon, Shannon R McCurdy, Richard Ambinder, Javier Bolaños-Meade, Leo Luznik, Ephraim J Fuchs, Richard J Jones, Kenneth R Cooke, Heather J Symons
Lower intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n=40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide (PT/Cy) from 2003-2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplant immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus...
November 22, 2016: Biology of Blood and Marrow Transplantation
Sinda Bigenzahn, Ines Pree, Christoph Klaus, Nina Pilat, Benedikt Mahr, Elisabeth Schwaiger, Patrick Nierlich, Friedrich Wrba, Thomas Wekerle
Mixed chimerism and tolerance can be successfully induced in rodents through allogeneic bone marrow transplantation (BMT) with costimulation blockade (CB), but varying success rates have been reported with distinct models and protocols. We therefore investigated the impact of minor antigen disparities on the induction of mixed chimerism and tolerance. C57BL/6 (H2(b)) mice received nonmyeloablative total body irradiation (3 Gy), costimulation blockade (anti-CD40L mAb and CTLA4Ig), and 2 × 10(7) bone marrow cells (BMC) from either of three donor strains: Balb/c (H2(d)) (MHC plus multiple minor histocompatibility antigen (mHAg) mismatched), B10...
2016: Journal of Immunology Research
Jeffrey M Dodd-O, Sudipto Ganguly, Ante Vulic, Angela Panoskaltsis-Mortari, John F McDyer, Leo Luznik
BACKGROUND: Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. METHODS: Using the major histocompatibility complex-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low-dose total body irradiation and posttransplant (donor) bone marrow, and splenocyte infusion followed by posttransplantation cyclophosphamide...
December 2016: Transplantation
Shannon R McCurdy, Yvette L Kasamon, Christopher G Kanakry, Javier Bolaños-Meade, Hua-Ling Tsai, Margaret M Showel, Jennifer A Kanakry, Heather J Symons, Ivana Gojo, B Douglas Smith, Maria P Bettinotti, William H Matsui, Amy E Dezern, Carol Ann Huff, Ivan Borrello, Keith W Pratz, Douglas E Gladstone, Lode J Swinnen, Robert A Brodsky, Mark J Levis, Richard F Ambinder, Ephraim J Fuchs, Gary L Rosner, Richard J Jones, Leo Luznik
Composite endpoints that not only encompass mortality and relapse, but other critical posttransplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, posttransplantation cyclophosphamide reduces severe graft-versus-host disease after allogeneic marrow transplantation, making its composite endpoints of particular interest. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrows and posttransplantation cyclophosphamide after myeloablative HLA-matched related (n= 192) or unrelated (n=120), or nonmyeloablative HLA-haploidentical (n = 372) donor transplantation; median follow up was 4 (range 0...
October 20, 2016: Haematologica
Raimon Duran-Struuck, Hugo P Sondermeijer, Leo Bühler, Paula Alonso-Guallart, Jonah Zitsman, Yojiro Kato, Anette Wu, Alicia N McMurchy, David Woodland, Adam Griesemer, Mercedes Martinez, Svetlan Boskovic, Tatsuo Kawai, A Benedict Cosimi, Cheng-Shie Wuu, Andrea Slate, Markus Mapara, Sam Baker, Rafal Tokarz, Vivette Dʼ Agati, Scott Hammer, Marcus Pereira, W Ian Lipkin, Thomas Wekerle, Megan Levings, Megan Sykes
BACKGROUND: Infusion of recipient regulatory T cells (Treg) promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic BMT with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. METHODS: CD4+CD25high Treg that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and MHC-mismatched BMT with or without Treg infusion...
November 15, 2016: Transplantation
Sandra Lange, Anne Steder, Doreen Killian, Gudrun Knuebel, Anett Sekora, Heike Vogel, Iris Lindner, Simone Dunkelmann, Friedrich Prall, Hugo Murua Escobar, Mathias Freund, Christian Junghanss
An intra-bone marrow (IBM) hematopoietic stem cell transplantation (HSCT) is assumed to optimize the homing process and therefore to improve engraftment as well as hematopoietic recovery compared with conventional i.v. HSCT. This study investigated the feasibility and efficacy of IBM HSCT after nonmyeloablative conditioning in an allogeneic canine HSCT model. Two study cohorts received IBM HSCT of either density gradient (IBM-I, n = 7) or buffy coat (IBM-II, n = 6) enriched bone marrow cells. An historical i...
November 2, 2016: Biology of Blood and Marrow Transplantation
Antonia M S Müller, Mareike Florek, Holbrook E K Kohrt, Natascha J Küpper, Alexander Filatenkov, Jessica A Linderman, Husein Hadeiba, Robert S Negrin, Judith A Shizuru
T cells are widely used to promote engraftment of hematopoietic stem cells (HSCs) during an allogeneic hematopoietic cell transplantation. Their role in overcoming barriers to HSC engraftment is thought to be particularly critical when patients receive reduced doses of preparative chemotherapy and/or radiation compared with standard transplantations. In this study, we sought to delineate the effects CD4(+) cells on engraftment and blood formation in a model that simulates clinical hematopoietic cell transplantation by transplanting MHC-matched, minor histocompatibility-mismatched grafts composed of purified HSCs, HSCs plus bulk T cells, or HSCs plus T cell subsets into mice conditioned with low-dose irradiation...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Aimee G Kim, Jesse D Vrecenak, Matthew M Boelig, Linda Eissenberg, Michael P Rettig, John S Riley, Matthew S Holt, Michael A Conner, Stavros P Loukogeorgakis, Haiying Li, John F DiPersio, Alan W Flake, William H Peranteau
In utero hematopoietic cell transplantation (IUHCT) is a novel nonmyeloablative approach that results in donor-specific tolerance and mixed allogeneic chimerism. Clinical application is limited by low levels of donor cell engraftment. Competition from endogenous hematopoietic stem cells (HSCs) for limited "space" in fetal hematopoietic organs remains a significant barrier to successful IUHCT. AMD3100, a CXCR4 inhibitor, and firategrast, an α4β1 and α4β7 integrin inhibitor (α4β1/7), have been shown to disrupt HSC retention in the postnatal hematopoietic niche...
November 17, 2016: Blood
V Bhatt, L Shune, E Lauer, M Lubin, S M Devlin, A Scaradavou, R Parameswaran, M A Perales, D M Ponce, S Mantha, N A Kernan, J N Barker
Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9-70 years) transplanted for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor (CNI)/mycophenolate mofetil. With a median 5.2-year (range 1.6-9.7 years) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10...
September 19, 2016: Bone Marrow Transplantation
Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S Allan, Joren C Madsen, Gilles Benichou, Rex-Neal Smith, Robert B Colvin, David H Sachs, A Benedict Cosimi, Tatsuo Kawai
Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen...
July 7, 2016: JCI Insight
Gaurav Goyal, Krishna Gundabolu, Saraschandra Vallabhajosyula, Peter T Silberstein, Vijaya Raj Bhatt
Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis...
June 2016: Therapeutic Advances in Hematology
Stephanie L Goff, Mark E Dudley, Deborah E Citrin, Robert P Somerville, John R Wunderlich, David N Danforth, Daniel A Zlott, James C Yang, Richard M Sherry, Udai S Kammula, Christopher A Klebanoff, Marybeth S Hughes, Nicholas P Restifo, Michelle M Langhan, Thomas E Shelton, Lily Lu, Mei Li M Kwong, Sadia Ilyas, Nicholas D Klemen, Eden C Payabyab, Kathleen E Morton, Mary Ann Toomey, Seth M Steinberg, Donald E White, Steven A Rosenberg
PURPOSE: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion...
July 10, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Moufida Ben Nasr, Roberto Bassi, Vera Usuelli, Alessandro Valderrama-Vasquez, Sara Tezza, Francesca D'Addio, Paolo Fiorina
Hematopoietic stem cells (HSCs) have been shown recently to hold much promise in curing autoimmune diseases. Newly diagnosed Type 1 diabetes individuals have been successfully reverted to normoglycemia by administration of autologous HSCs in association with a nonmyeloablative regimen (antithymocyte globulin + cyclophasmide). Furthermore, recent trials reported positive results by using HSCs in treatment of systemic sclerosis, multiple sclerosis and rheumatoid arthritis as well. Early data suggested that HSCs possess immunological properties that may be harnessed to alleviate the symptoms of individuals with autoimmune disorders and possibly induce remission of autoimmune diseases...
June 2016: Regenerative Medicine
Andrea Bacigalupo, Simona Sica
The use of high dose posttransplant cyclophosphamide (PT-CY) introduced by the Baltimore group approximately 10 years ago has been rapidly adopted worldwide and is becoming a standard for patients undergoing unmanipulated haploidentical (HAPLO) transplants. PT-CY has been used following nonmyeloablative as well as myeloablative conditioning regimens, for bone marrow or peripheral blood grafts, for patients with malignant and nonmalignant disorders. Retrospective comparisons of HAPLO grafts with conventional sibling and unrelated donor grafts have been published and suggest comparable outcome...
2016: Advances in Hematology
Rainer Storb, Brenda M Sandmaier
Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens...
May 2016: Haematologica
Sabrina Peters, Christian Junghanss, Anne Knueppel, Hugo Murua Escobar, Catrin Roolf, Gudrun Knuebel, Anett Sekora, Iris Lindner, Ludwig Jonas, Mathias Freund, Sandra Lange
BACKGROUND: Langerhans cells (LC) are bone marrow-derived cells in the skin. The LC donor/recipient chimerism is assumed to influence the incidence and severity of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). In nonmyeloablative (NM) HSCT the appearance of acute GVHD is delayed when compared with myeloablative conditioning. Therefore, we examined the development of LC chimerism in a NM canine HSCT model. METHODS: 2 Gy conditioned dogs received bone marrow from dog leukocyte antigen identical littermates...
2016: BMC Hematology
Suk See De Ravin, Xiaolin Wu, Susan Moir, Sandra Anaya-O'Brien, Nana Kwatemaa, Patricia Littel, Narda Theobald, Uimook Choi, Ling Su, Martha Marquesen, Dianne Hilligoss, Janet Lee, Clarissa M Buckner, Kol A Zarember, Geraldine O'Connor, Daniel McVicar, Douglas Kuhns, Robert E Throm, Sheng Zhou, Luigi D Notarangelo, I Celine Hanson, Mort J Cowan, Elizabeth Kang, Coleen Hadigan, Michael Meagher, John T Gray, Brian P Sorrentino, Harry L Malech
X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy...
April 20, 2016: Science Translational Medicine
Stephen M Ansell
DISEASE OVERVIEW: Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,050 new patients annually and representing approximately 11.2% of all lymphomas in the United States. DIAGNOSIS: HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL...
June 2016: American Journal of Hematology
Scott R Solomon, Melhem Solh, Lawrence E Morris, H Kent Holland, Asad Bashey
Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT). In an attempt to reduce relapse, we have developed a myeloablative (MA) haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy) and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based (n = 20) and a TBI-based MA preparative regimen (n = 30), and analyze a larger cohort of 64 patients receiving MA haplo-HSCT...
2016: Advances in Hematology
Dorothy R McKenna, Matthew R Sullivan, John M Hill, Christopher H Lowrey, Jeremiah R Brown, Joshua Hickman, Kenneth R Meehan
BACKGROUND: About 1 in 7 of all hospitalized patients is readmitted within 30 days of discharge. The cost of readmissions is significant, with Medicare readmissions alone costing the health care system an estimated $28 billion a year. OBJECTIVE: To identify the rates of and causes for readmission within 100 days of patients receiving a hematopoietic stem cell transplant. METHODS: We performed a retrospective review of 235 consecutive transplant recipients (autologous, n = 144; allogeneic, n = 91) to determine rates and causes for readmission within 100 days of patients receiving a transplant...
September 2015: Journal of Community and Supportive Oncology
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