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High dose cyclophosphamide for graft versus host disease prevention

Sameh Gaballa, Isabell Ge, Riad El Fakih, Jonathan E Brammer, Piyanuch Kongtim, Ciprian Tomuleasa, Sa A Wang, Dean Lee, Demetrios Petropoulos, Kai Cao, Gabriela Rondon, Julianne Chen, Aimee Hammerstrom, Lindsey Lombardi, Gheath Alatrash, Martin Korbling, Betul Oran, Partow Kebriaei, Sairah Ahmed, Nina Shah, Katayoun Rezvani, David Marin, Qaiser Bashir, Amin Alousi, Yago Nieto, Muzaffar Qazilbash, Chitra Hosing, Uday Popat, Elizabeth J Shpall, Issa Khouri, Richard E Champlin, Stefan O Ciurea
BACKGROUND: High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients. METHODS: A parallel, 2-arm, nonrandomized phase 2 clinical trial was conducted of melphalan-based reduced-intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high-risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT...
July 12, 2016: Cancer
Massimo Berger, Edoardo Lanino, Simone Cesaro, Marco Zecca, Elena Vassallo, Maura Faraci, Massimiliano De Bortoli, Veronica Barat, Arcangelo Prete, Franca Fagioli
Post-transplant high-dose cyclophosphamide (PTCy) is a novel approach to prevent graft-versus-host disease (GVHD) and rejection in patients given haploidentical hematopoietic stem cell transplantation (HSCT). Thirty-three patients with high-risk hematologic malignancies and lacking a match-related or -unrelated donor were treated with PTCy haploidentical HSCT in 5 Italian AIEOP centers. Nineteen patients had a nonmyeloablative preparative regimen (57%), and 14 patients received a full myeloablative conditioning regimen (43%)...
May 2016: Biology of Blood and Marrow Transplantation
Marco Mielcarek, Terry Furlong, Paul V O'Donnell, Barry E Storer, Jeannine S McCune, Rainer Storb, Paul A Carpenter, Mary E D Flowers, Frederick R Appelbaum, Paul J Martin
The cumulative incidence of National Institutes of Health (NIH)-defined chronic graft-versus-host disease (GVHD) requiring systemic treatment is ∼35% at 1 year after transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized blood cells from HLA-matched related or unrelated donors. We hypothesized that high-dose cyclophosphamide given after G-CSF-mobilized blood cell transplantation would reduce the cumulative 1-year incidence of chronic GVHD to 15% or less. Forty-three patients with high-risk hematologic malignancies (median age, 43 years) were enrolled between December 2011 and September 2013...
March 17, 2016: Blood
Ahmad-Samer Al-Homsi, Kelli Cole, Marlee Bogema, Ulrich Duffner, Stephanie Williams, Aly Mageed
An effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells...
July 2015: Biology of Blood and Marrow Transplantation
Christopher G Kanakry, Hua-Ling Tsai, Javier Bolaños-Meade, B Douglas Smith, Ivana Gojo, Jennifer A Kanakry, Yvette L Kasamon, Douglas E Gladstone, William Matsui, Ivan Borrello, Carol Ann Huff, Lode J Swinnen, Jonathan D Powell, Keith W Pratz, Amy E DeZern, Margaret M Showel, Michael A McDevitt, Robert A Brodsky, Mark J Levis, Richard F Ambinder, Ephraim J Fuchs, Gary L Rosner, Richard J Jones, Leo Luznik
High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or -unrelated T-cell-replete allografting...
December 11, 2014: Blood
Ahmad Samer Al-Homsi, Tara S Roy, Kelli Cole, Yuxin Feng, Ulrich Duffner
Cyclophosphamide's lack of hematopoietic stem cell toxicity and its unique effects on the immune system have prompted several investigators to explore its potential for the prevention of graft-versus-host disease (GVHD). In haploidentical hematopoietic stem cell transplants, post-transplant cyclophosphamide together with standard prophylaxis reduces the incidence of GVHD to acceptable rates without the need for T cell depletion. In matched related and unrelated donor settings, cyclophosphamide alone has produced encouraging results...
April 2015: Biology of Blood and Marrow Transplantation
Nada Hamad, Ryan Del Bel, Hans A Messner, Dennis Kim, John Kuruvilla, Jeffrey H Lipton, Jieun Uhm, Matthew Seftel, Naheed Alam, Wei Xu, Vikas Gupta
Graft-versus-host disease (GVHD) has no therapeutic benefit after hematopoietic cell transplantation (HCT) for patients with acquired aplastic anemia (AA), and its prevention is highly desirable. We designed a conditioning regimen using an intermediate dose of alemtuzumab (50 to 60 mg) and describe our institutional experience of 41 patients who underwent HCT for AA. The median age at HCT was 37 years (range, 17 to 59). The conditioning regimen was high-dose cyclophosphamide (n = 9) or fludarabine based (n = 32)...
November 2014: Biology of Blood and Marrow Transplantation
Sandeep Soni, Thomas G Gross, Hemalatha Rangarajan, K Scott Baker, Mollie Sturm, Melissa Rhodes
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) in children. Despite excellent outcomes of matched sibling donor (MSD) HSCT, there is still 5-10% chance of rejection and transplant related mortality (TRM) with 12-23% incidence of graft versus host disease (GVHD). We postulated that an intermediate dose of rabbit anti-thymocyte globulin (r-ATG, 10 mg/kg cumulative) would be effective in preventing both rejection and GVHD...
September 2014: Pediatric Blood & Cancer
Ephraim J Fuchs
Tolerance induction and alloreactivity can be applied to the clinic for the transplantation of solid organs and in the treatment of human cancers respectively. Hematopoietic chimerism, the stable coexistence of host and donor blood cells, guarantees that a solid organ from the same donor will be tolerated without a requirement for maintenance immunosuppression, and it also serves as a platform for the adoptive immunotherapy of hematologic malignancies using donor lymphocyte infusions. This review focuses on clinically relevant methods for inducing hematopoietic chimerism and transplantation tolerance, with a special emphasis on reduced intensity transplantation conditioning and high dose, post-transplantation cyclophosphamide to prevent graft rejection and graft-versus-host disease (GVHD)...
March 2014: Immunological Reviews
Christopher G Kanakry, Sudipto Ganguly, Marianna Zahurak, Javier Bolaños-Meade, Christopher Thoburn, Brandy Perkins, Ephraim J Fuchs, Richard J Jones, Allan D Hess, Leo Luznik
High-dose, posttransplantation cyclophosphamide (PTCy) is an effective strategy for preventing graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT). However, the mechanisms by which PTCy modulates alloimmune responses are not well understood. We studied early T cell reconstitution in patients undergoing alloBMT with PTCy and the effects of mafosfamide, a cyclophosphamide (Cy) analog, on CD4(+) T cells in allogeneic mixed lymphocyte reactions (MLRs) in vitro. Patients exhibited reductions in naïve, potentially alloreactive conventional CD4(+) T cells with relative preservation of memory CD4(+)Foxp3(+) T cells...
November 13, 2013: Science Translational Medicine
Leo Luznik, Paul V O'Donnell, Ephraim J Fuchs
Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative therapy for many hematologic and immunologic diseases. Further, partial or full donor hematopoietic chimerism following alloSCT may be sufficient to guarantee immunologic tolerance to solid organs from the same donor, obviating any requirement for prolonged pharmacologic immunosuppression. Despite alloSCT's potential, the procedure is beset by two major limitations. The first relates to the procedure's toxicity, including conditioning regimen toxicity, graft-versus-host disease (GVHD), and infection...
December 2012: Seminars in Oncology
Ulas Darda Bayraktar, Marcos de Lima, Stefan Octavian Ciurea
Hematopoietic stem cell transplantation from haploidentical donors is an attractive method of transplantation due to the immediate donor availability, ease of stem cell procurement and the possibility to collect additional donor cells for cellular therapy, if needed. Historically, maintaining T-cells in the graft has been associated with very high rates of graft-versus-host disease, while T-cell depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and delayed immune reconstitution post-transplant...
2011: Revista Brasileira de Hematologia e Hemoterapia
Emin Kansu
Hemostatic changes and thrombotic events are frequent in patients undergoing stem cell transplantation. Arterial and venous thromboses are major causes of morbidity and mortality. Thrombotic complications can be classified into four groups including: catheter-related thrombosis, venous thromboembolic (VTE) events, sinusoidal obstructive syndrome (SOS)/veno-occlusive disease, and transplant-associated thrombotic microangiopathy (TAM). The incidence of catheter-related thrombosis is 8-20% in patients undergoing autologous hematopoietic stem cell transplantation (HSCT), and the incidence is low in syngeneic and allogeneic transplant patients...
April 2012: Hematology (Amsterdam, Netherlands)
Ulas D Bayraktar, Richard E Champlin, Stefan O Ciurea
Haploidentical stem cell transplantation is an attractive form of transplantation because of the immediate donor availability, ease of stem cell procurement, and the possibility to further collect donor cells for cellular therapy. Historically, maintaining T cells in the graft has been associated with very high rates of graft-versus-host-disease (GVHD), whereas T cell-depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and nonrelapse mortality related to infectious complications as a result of delayed immune reconstitution posttransplantation...
March 2012: Biology of Blood and Marrow Transplantation
G A Novichkova, M A Maschan, I P Shipitsyna, Iu V Skvortsova, M I Persiantseva, L L Lebedeva, V O Bobrynina, D D Baĭdil'dina, O V Goronkova, G G Solopova, L A Khachatrian, U N Petrova, E V Suntsova, I I Kalinina, V V Sinitsyna, E V Skorobogatova, D N Balashov, Z M Dyshlevaia, L N Shelikhova, E E Kurnikova, P E Trakhtman, A A Maschan
AIM: To analyze the efficiency of transplantation of the bone marrow from a HLA-compatible unrelated donor and continued immunosuppressive therapy (IST) in children with aplastic anemia (AA) unresponsive to 2 courses of IST. SUBJECTS AND METHODS: The study enrolled 14 children aged 2-16 years (median 9 years). A control group comprised 26 patients in whom IST was continued. The median interval between the diagnosis of AA and transplantation was 26 months (9-156 months)...
2010: Terapevticheskiĭ Arkhiv
Leo Luznik, Richard J Jones, Ephraim J Fuchs
PURPOSE OF REVIEW: Administration of high-dose cyclophosphamide after transplantation inhibits both graft rejection and graft-versus-host disease (GvHD) in mouse models of allogeneic blood or marrow transplantation (alloBMT). This strategy has recently been adapted to human transplantation. RECENT FINDINGS: The safety and efficacy of high-dose posttransplantation cyclophosphamide, when given in combination with tacrolimus and mycophenolate mofetil, was first demonstrated after nonmyeloablative conditioning and allografting using human leukocyte antigen (HLA)-mismatched related donors...
November 2010: Current Opinion in Hematology
Hyoung Jin Kang, Hee Young Shin, Jun Eun Park, Nak Gyun Chung, Bin Cho, Hack Ki Kim, Sun Young Kim, Young Ho Lee, Young Tak Lim, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Ho Joon Im, Jong Jin Seo, Sang Kyu Park, Hyo Seop Ahn
Antithymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective for preventing graft-versus-host disease (GVHD) and the rejection of organ transplants. After the promising results of our preliminary study, we conducted a phase II prospective multicenter clinical trial using a fludarabine (Flu), cyclophosphamide (Cy), and thymoglobulin conditioning regimen to allow good engraftment in patients who underwent unrelated transplantation for SAA...
November 2010: Biology of Blood and Marrow Transplantation
Leo Luznik, Ephraim J Fuchs
Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloHSCT. High-dose, post-transplantation Cy facilitates partially HLA-mismatched HSCT without severe GVHD and is effective as sole prophylaxis of GVHD after HLA-matched alloHSCT...
July 2010: Immunologic Research
Mei Guo, Zhao Sun, Qi-Yun Sun, Qin Han, Chang-Lin Yu, Dan-Hong Wang, Jian-Hui Qiao, Bin Chen, Wan-Jun Sun, Kai-Xun Hu, Guang-Xian Liu, Bing Liu, Robert Chunhua Zhao, Huisheng Ai
Severe graft-versus-host disease (GVHD) and graft rejection still remain major complications of haploidentical nonmyeloablative (NMA) stem cell transplantation. Recent studies have shown that bone marrow-derived mesenchymal stem cells (MSCs) possess immunomodulatory capacity and may promote hematopoietic engraftment. The purpose of this study was to observe if the new strategy, which included a haploidentical peripheral blood stem cell transplantation (PBSCT) combined with MSCs, modified NMA conditioning, and GVHD prophylaxis would improve donor engraftment and prevent severe GVHD...
August 2009: Biology of Blood and Marrow Transplantation
Sandra K Call, Kimberly A Kasow, Raymond Barfield, Renee Madden, Wing Leung, Edwin Horwitz, Paul Woodard, John C Panetta, Sharyn Baker, Rupert Handgretinger, John Rodman, Gregory A Hale
Rabbit antithymocyte globulin (rATG; Thymoglobulin) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Children's Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG...
February 2009: Biology of Blood and Marrow Transplantation
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