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High dose cyclophosphamide for graft versus host disease prevention

Mark Parta, Nirali N Shah, Kristin Baird, Hind Rafei, Katherine R Calvo, Thomas Hughes, Kristen Cole, Meg Kenyon, Bazetta Blacklock Schuver, Jennifer Cuellar-Rodriguez, Christa S Zerbe, Steven M Holland, Dennis D Hickstein
Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients...
February 3, 2018: Biology of Blood and Marrow Transplantation
Courtney D Fitzhugh, Matthew M Hsieh, Tiffani Taylor, Wynona Coles, Katherine Roskom, Delon Wilson, Elizabeth Wright, Neal Jeffries, Christopher J Gamper, Jonathan Powell, Leo Luznik, John F Tisdale
Peripheral blood stem cell transplantation (PBSCT) offers a curative option for sickle cell disease (SCD). Although HLA-matched sibling transplantation is promising, the vast majority of patients lack such a donor. We sought to develop a novel nonmyeloablative HLA-haploidentical PBSCT approach that could safely be used for patients with severe organ damage. Based on findings in our preclinical model, we developed a phase 1/2 trial using alemtuzumab, 400 cGy total body irradiation, and escalating doses of posttransplant cyclophosphamide (PT-Cy): 0 mg/kg in cohort 1, 50 mg/kg in cohort 2, and 100 mg/kg in cohort 3...
April 25, 2017: Blood Advances
Yu Wang, Ying-Jun Chang, Lu Chen, Lan-Ping Xu, Zhi-Lei Bian, Xiao-Hui Zhang, Chen-Hua Yan, Kai-Yan Liu, Xiao-Jun Huang
Use of high-dose, post-transplant cyclophosphamide (PTCy) results in low rates of graft-versus-host-disease (GVHD) and favorable immune reconstitution, although with higher rates of relapse and somewhat high rates of graft failure. We hypothesized that permissible dose reduction of PTCy might be feasible. The current study attempts to establish a murine model and focus on regulatory T cells (Tregs) to clarify the immunological mechanisms for GVHD prevention by low-dose PTCy. In addition, a prospective, clinical cohort study in haploidentical, T-cell replete transplantation is initiated to support the rational...
2017: Oncoimmunology
Biju George, Nisham Pn, Anup J Devasia, Uday Kulkarni, Anu Korula, Kavitha M Lakshmi, Aby Abraham, Alok Srivastava, Vikram Mathews
High-dose cyclophosphamide (PTCY) after allogeneic hematopoietic cell transplantation (HSCT) has been shown to be effective in preventing graft-versus-host disease (GVHD) after HLA-matched bone marrow transplantation. We performed a phase II study of PTCY given at 50 mg/kg i.v. on days 3 and 4 as the sole GVHD prophylaxis after HSCT for severe aplastic anemia (SAA) in patients receiving granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts from HLA-matched related donors after conditioning with fludarabine, CY, and single-dose total body irradiation...
March 2018: Biology of Blood and Marrow Transplantation
Nicolas J Llosa, Kenneth R Cooke, Allen R Chen, Christopher J Gamper, Orly R Klein, Elias T Zambidis, Brandon Luber, Gary Rosner, Nicholas Siegel, Mary Jo Holuba, Nancy Robey, Masanori Hayashi, Richard J Jones, Ephraim Fuchs, Matthias Holdhoff, David M Loeb, Heather J Symons
High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus...
December 2017: Biology of Blood and Marrow Transplantation
Enkhtsetseg Purev, Xin Tian, Georg Aue, Jeremy Pantin, Phuong Vo, Reem Shalabi, Robert N Reger, Lisa Cook, Catalina Ramos, Elena Cho, Tat'yana Worthy, Hanh Khuu, David Stroncek, Neal S Young, Richard W Childs
Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA) unresponsive to immunosuppressive therapy. To reduce chronic graft-versus-host disease (GVHD), which occurs more frequently after peripheral blood stem cell (PBSC) transplantation compared to bone-marrow transplantation (BMT), and to prevent graft rejection, we developed a novel partial T-cell depleted transplant that infuses high numbers of granulocyte colony-stimulating factor-mobilized CD34(+) selected PBSCs combined with a BMT-equivalent dose of non-mobilized donor T-cells...
March 2017: British Journal of Haematology
Franco Aversa, Lucia Prezioso, Ilenia Manfra, Federica Galaverna, Angelica Spolzino, Alessandro Monti
The advantage of using a Human Leukocyte Antigen (HLA)-mismatched related donor is that almost every patient who does not have an HLA-identical donor or who urgently needs hematopoietic stem cell transplantation (HSCT) has at least one family member with whom shares one haplotype (haploidentical) and who is promptly available as a donor. The major challenge of haplo-HSCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD). Advances in graft processing and pharmacologic prophylaxis of GVHD have reduced these risks and have made haplo-HSCT a viable alternative for patients lacking a matched donor...
2016: Mediterranean Journal of Hematology and Infectious Diseases
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...
November 15, 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)
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