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1
Kernan, NA, C. Bordignon, G. Heller, I. Cunningham, H. Castro-Malaspina, B. Shank, N. Flomenberg, J. Burns, SY Yang, and P. Black. "Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia: I. Analysis of risk factors and results of secondary transplants." Blood 74, no. 6 (November 1, 1989): 2227–36. http://dx.doi.org/10.1182/blood.v74.6.2227.bloodjournal7462227.
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Risk factors for graft failure were analyzed in 122 recipients of an allogeneic T-cell-depleted human leukocyte antigen (HLA)-identical sibling marrow transplant as treatment for leukemia. In each case pretransplant immunosuppression included 1,375 to 1,500 cGy hyperfractionated total body irradiation and cyclophosphamide (60 mg/kg/d x 2). No patient received immunosuppression prosttransplant for graft-versus-host disease (GVHD) prophylaxis. Nineteen patients in this group experienced graft failure. The major factors associated with graft failure were transplants from male donors and the age of the patient (or donor). Among male recipients of male donor-derived grafts a low dose per kilogram of nucleated cells, progenitor cells (colony forming unit-GM) and T cells was also associated with graft failure. Additional irradiation to 1,500 cGy, high dose corticosteroids posttransplant, and additional peripheral blood donor T cells did not decrease the incidence of graft failure. In addition, type of leukemia, time from diagnosis to transplant, an intact spleen, or the presence of antidonor leukocyte antibodies did not correlate with graft failure. To ensure engraftment of secondary transplants, further immunosuppression was necessary but was poorly tolerated. However, engraftment and survival could be achieved with an immunosuppressive regimen in which antithymocyte globulin and high dose methylprednisolone were administered both before and after infusions of secondary partially T- cell-depleted marrow grafts.
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Kernan, NA, C. Bordignon, G. Heller, I. Cunningham, H. Castro-Malaspina, B. Shank, N. Flomenberg, J. Burns, SY Yang, and P. Black. "Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia: I. Analysis of risk factors and results of secondary transplants." Blood 74, no. 6 (November 1, 1989): 2227–36. http://dx.doi.org/10.1182/blood.v74.6.2227.2227.
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Abstract Risk factors for graft failure were analyzed in 122 recipients of an allogeneic T-cell-depleted human leukocyte antigen (HLA)-identical sibling marrow transplant as treatment for leukemia. In each case pretransplant immunosuppression included 1,375 to 1,500 cGy hyperfractionated total body irradiation and cyclophosphamide (60 mg/kg/d x 2). No patient received immunosuppression prosttransplant for graft-versus-host disease (GVHD) prophylaxis. Nineteen patients in this group experienced graft failure. The major factors associated with graft failure were transplants from male donors and the age of the patient (or donor). Among male recipients of male donor-derived grafts a low dose per kilogram of nucleated cells, progenitor cells (colony forming unit-GM) and T cells was also associated with graft failure. Additional irradiation to 1,500 cGy, high dose corticosteroids posttransplant, and additional peripheral blood donor T cells did not decrease the incidence of graft failure. In addition, type of leukemia, time from diagnosis to transplant, an intact spleen, or the presence of antidonor leukocyte antibodies did not correlate with graft failure. To ensure engraftment of secondary transplants, further immunosuppression was necessary but was poorly tolerated. However, engraftment and survival could be achieved with an immunosuppressive regimen in which antithymocyte globulin and high dose methylprednisolone were administered both before and after infusions of secondary partially T- cell-depleted marrow grafts.
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Self, Michael, Ernest Dunn, John Cox, and Karl Brinker. "Managing Breast Cancer in the Renal Transplant Patient: A Unique Dilemma." American Surgeon 72, no. 2 (February 2006): 150–53. http://dx.doi.org/10.1177/000313480607200211.
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Improvements in immunosuppression have increased patient and graft survival in transplant recipients. As a result, there is greater risk of neoplastic processes such as breast cancer. Treatment in this population is complicated by the necessary immunosuppression, vascular accesses, and transplant grafts. General surgeons may expect to encounter more of these complex patients in the community setting. We sought to evaluate the surgical treatment of breast cancer in patients with renal transplants. Hospital and private physician records were queried to identify patients who developed breast cancer after a renal or pancreatic/renal transplantation. These charts were reviewed for demographics, type of breast cancer and treatment, location of dialysis access, and complications. From June 1, 1994, to May 31, 2004, 14 patients were identified. Eight patients had functioning transplants. All patients underwent operative interventions. Ten patients underwent adjuvant treatment. Three had functioning transplants and chose not to risk the graft with cessation of immunotherapy. However, no patient with functioning transplants who underwent chemotherapy developed organ failure. Breast cancer after transplantation poses a unique dilemma. The threat of transplanted organ failure is a major concern to these patients and often supersedes adjuvant therapies.
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Trumble, Thomas E. "Peripheral Nerve Transplantation: The Effects of Predegenerated Grafts and Immunosuppression." Journal of Neural Transplantation and Plasticity 3, no. 1 (1992): 39–49. http://dx.doi.org/10.1155/np.1992.39.
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Research involving nerve transplantation has shown that tissue rejection limits the neurologic recovery unless the host is immunosuppressed. This study investigates an alternative to permanent or temporary immunosuppression using a rat model with nerve transplants from Brown- Norway rat donors to bridge defects in the sciatic nerve of Lewis rat recipients as these two inbred strains differ at both major and minor histocompatibility loci.The specific aim of this study was to evaluate if predegenerated nerve grafts decreased the tissue rejection and improved the neurologic recovery of animals with allogenic nerve grafts to avoid the problems associated with either short- or long-term immunosuppression. The animals in the experimental groups received cyclosporin-A, predegencrated grafts, both, or neither. The predegenerated grafts were produced by division of the nerve three weeks prior to grafting to allow for Wallerian degeneration to occur. The outcome was assessed by measurements stressing functional recovery (sensory testing, gait analysis, joint flexion contracture), studies of muscle recovery (muscle weight and hydroxyproline concentration), and histologic studies (axonal counts and inflammatory reaction). The animals receiving the predegenerated grafts without cyclosporin did have an improved recovery (joint flexion contracture 35° ± 8 ° and hydroxyproline ratio 1.52 ± 0.16) as compared to the joint flexion contractures and hydroxyproline ratios of the allograft group of animals without either cyclosporin- A or pretreatment and the ungrafted control group (47° ± 18°, 1.68 ± 0.34, and 53° ±15° ,4.50 ± 0.27, respectively, p < 0.01). However, all the isograft groups and allograft groups with cyclosporin-A, regardless of whether the graft had been predegenerated or not, had greater neurologic recovery than the allograft group with predegenerated grafts but without cyclosporin-A by the same parameters (p < 0.01). Allograft groups with short-term immunosuppression with cyclosporin-A did as well as isograft groups, and isograft groups with predegenerated grafts did not do any better than isografts without pretreatment (p <0.01).Clinical Relevance:Predegenerated nerve allografts will allow for greater neurologic recovery than standard nerve allografts avoiding the complications of immunosuppression, but the level of recovery is less than that of recipients of nerve allografts with immunosuppression. Nerve transplants would avoid the problems of neurologic deficits at the donor site and allow multiple large deficits to be treated easily.
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Mathes, David, Scott Stoll Graves, George E. Georges, Christian Kuhr, Jeff Chang, Tiffany Butts, and Rainer Storb. "Long-Term Tolerance to Kidney Allografts After Induced Rejection of Donor Hematopoietic Chimerism in a Preclinical Canine Model." Blood 120, no. 21 (November 16, 2012): 2991. http://dx.doi.org/10.1182/blood.v120.21.2991.2991.
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Abstract Abstract 2991 Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance towards solid organ grafts. However, this procedure can result in graft-versus-host disease (GVHD) thereby limiting its application. Here we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft. Recipient dogs were given 2 Gy total body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen-identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2 Gy TBI and given autologous granulocyte-colony stimulating factor-mobilized leukocytes (recipient leukocyte infusion) that had been collected before marrow transplant. Dogs receiving a second TBI and recipient leukocyte infusion without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and recipient leukocyte infusion, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than one year. Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This model has potential applications in understanding the mechanism of split tolerance. This finding may have application towards minimizing the risk of GVHD in solid organ transplant patients given hematopoietic cell transplantation from HLA-identical donors. Disclosures: No relevant conflicts of interest to declare.
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Kjøsen, Gisle, Kristina Rydenfelt, Rune Horneland, Einar Martin Aandahl, Pål-Dag Line, Eric Dorenberg, Audun Elnæs Berstad, et al. "Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study." PLOS ONE 16, no. 3 (March 11, 2021): e0247615. http://dx.doi.org/10.1371/journal.pone.0247615.
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Background Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged. Methods To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1–2 hours. Results Nine patients with graft venous thrombosis had significant lactate and lactate–to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas. Conclusions Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.
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Ghoneim, Mohamed A., Mohamed A. Bakr, Ayman F. Refaie, Ahmed I. Akl, Ahmed A. Shokeir, Ahmed B. Shehab El-Dein, Hesham M. Ammar, Amani M. Ismail, Hussein A. Sheashaa, and Mahmoud A. El-Baz. "Factors Affecting Graft Survival among Patients Receiving Kidneys from Live Donors: A Single-Center Experience." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/912413.
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Introduction. The aim of this report is to study the graft and patient survival in a large cohort of recipients with an analysis of factors that may affect the final outcomes.Methods. Between March 1976 and March 2008, 1967 consecutive live-donor renal transplants were carried out. Various variables that may have an impact on patients and/or graft survival were studied in two steps. Initially, a univariate analysis was carried out. Thereafter, significant variables were embedded in a stepwise regression analysis.Results. The overall graft survival was 86.7% and 65.5%, at 5 and 10 years, respectively. The projected half-life for grafts was 17.5 years and for patients was 22 years. Five factors had an independent negative impact on graft survival: donor's age, genetic considerations, the type of primary immunosuppression, number of acute rejection episodes, and total steroid dose during the first 3 months after transplantation.Conclusions. Despite refinements in tissue matching techniques and improvements in immunosuppression protocols, an important proportion of grafts is still lost following living donor kidney transplantation, presumably due to chronic allograft nephropathy.
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Bushell, Andrew, and Kathryn J. Wood. "Permanent survival of organ transplants without immunosuppression: Experimental approaches and possibilities for tolerance induction in clinical transplantation." Expert Reviews in Molecular Medicine 1, no. 17 (October 29, 1999): 1–31. http://dx.doi.org/10.1017/s1462399499001179.
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During the past 30 years, organ transplantation has developed from a highly experimental procedure into an important part of routine clinical practice. This is reflected by the fact that graft survival times, which were once considered in terms of days or weeks, are now measured in terms of years or decades, with enormous corresponding benefits for the patient. Much of this improvement is due to the development of sophisticated immunosuppressive drugs that inhibit the rejection response mediated by the immune system of the recipient. However, almost without exception, all of the grafts that are transplanted from one genetically disparate individual to another are eventually rejected. The Holy Grail in transplantation is the development of protocols that lead to transplantation tolerance and provide stable graft function without long-term drug therapy. In this article, we have discussed the need for alternatives to current immunosuppression and reviewed the results of animal models, which suggest that long-term stable tolerance is an achievable goal.
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Ricordi, Camillo, Norico Murase, Cristiana Rastellini, Roubik Behboo, Anthony J. Demetris, and Thomas E. Starzl. "Indefinite Survival of Rat Islet Allografts following Infusion of Donor Bone Marrow without Cytoablation." Cell Transplantation 5, no. 1 (January 1996): 53–55. http://dx.doi.org/10.1177/096368979600500110.
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We have tested the effect of donor bone marrow cell (DBMC) infusion on the survival of pancreatic islet allografts in the rat, without the use of cytoablative recipient conditioning. Lewis and diabetic Brown Norway rats were used as donors and recipients, respectively. Donor islets were placed beneath the left renal capsule. Infusion of DBMC and temporary immunosuppression followed by delayed islet transplantation resulted in indefinite survival of all islet grafts (MST >180 days). Control animals demonstrated recurrent hyperglycemia (islet allografts rejection). Donor bone marrow derived cells were detected in the spleen and cervical lymph nodes of BN recipients of LEW bone marrow but not in the recipients of islet transplants alone. Second set full thickness skin grafts were performed in normal BN and in recipients of a previously successful ITX. Donor specific skin grafts were accepted in the animals that had received DBMC 40 days before the islet allograft, while animals receiving DBMC at the time of the islet allograft rejected the donor specific skin graft similarly to the controls. However, these animals did not reject a second set donor-specific islet transplant. The results indicate that radiation conditioning of the recipients was not necessary to induce microchimerism and graft acceptance in this rodent model of islet allotransplantation.
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Kozlowska, Urszula, Aleksandra Klimczak, Karolina Anna Bednarowicz, Tomasz Zalewski, Natalia Rozwadowska, Katarzyna Chojnacka, Stefan Jurga, Eytan R. Barnea, and Maciej K. Kurpisz. "Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo—Is Immunosuppression Mandatory?" Cells 10, no. 7 (July 16, 2021): 1804. http://dx.doi.org/10.3390/cells10071804.
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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.
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Fleissig, Yoram Y., Jason E. Beare, Amanda J. LeBlanc, and Christina L. Kaufman. "Evolution of the rat hind limb transplant as an experimental model of vascularized composite allotransplantation: Approaches and advantages." SAGE Open Medicine 8 (January 2020): 205031212096872. http://dx.doi.org/10.1177/2050312120968721.
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As clinical experience with surgical techniques and immunosuppression in vascularized composite allotransplantation recipients has accumulated, vascularized composite allotransplantation for hand and face have become standard of care in some countries for select patients who have experienced catastrophic tissue loss. Experience to date suggests that clinical vascularized composite allotransplantation grafts undergo the same processes of allograft rejection as solid organ grafts. Nonetheless, there are some distinct differences, especially with respect to the immunologic influence of the skin and how the graft is affected by environmental and traumatic insults. Understanding the mechanisms around these similarities and differences has the potential to not only improve vascularized composite allotransplantation outcomes but also outcomes for all types of transplants and to contribute to our understanding of how complex systems of immunity and function work together. A distinct disadvantage in the study of upper extremity vascularized composite allotransplantation recipients is the low number of clinical transplants performed each year. As upper extremity transplantation is a quality of life rather than a lifesaving transplant, these numbers are not likely to increase significantly until the risks of systemic immunosuppression can be reduced. As such, experimental models of vascularized composite allotransplantation are essential to test hypotheses regarding unique characteristics of graft rejection and acceptance of vascularized composite allotransplantation allografts. Rat hind limb vascularized composite allotransplantation models have been widely used to address these questions and provide essential proof-of-concept findings which can then be extended to other experimental models, including mice and large animal models, as new concepts are translated to the clinic. Here, we review the large body of rat hind limb vascularized composite allotransplantation models in the literature, with a focus on the various surgical models that have been developed, contrasting the characteristics of the specific model and how they have been applied. We hope that this review will assist other researchers in choosing the most appropriate rat hind limb transplantation model for their scientific interests.
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Markiewicz-Kijewska, Małgorzata, Piotr Kaliciński, Juan Torres Canizales, Angelo Di Giorgio, Ulrich Baumann, Carl Jorns, Alastair Baker, et al. "ABO Incompatible Liver Transplantation in Children: A 20 Year Experience from Centres in the TransplantChild European Reference Network." Children 8, no. 9 (August 31, 2021): 760. http://dx.doi.org/10.3390/children8090760.
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An increasing number of AB0-incompatible (AB0i) liver transplantations (LT) are being undertaken internationally in recent years due to organ shortages and the need for urgent transplantation. The aim of our study was establish the value of ABOi LT from available retrospective results of AB0i pediatric liver transplantations performed in European reference centers now belonging to the TransplantChild, European Reference Network (ERN). Data from medical records were analyzed, including demographic data, diagnosis, urgency of transplantation, time on the waiting list, PELD/MELD score, desensitization procedures, immunosuppression, selected post-transplant complications, and patient and graft survival. A total of 142 patients (pts) with transplants between 1986 and 2018 in 8 European transplant centers were included in the study. The indications for liver transplantation were: cholestatic diseases in 62 pts, acute liver failure in 42 pts, and other conditions in the remaining 38 pts. Sixty-six patients received grafts from living donors, and seventy-six received grafts from deceased donors. Both patient and graft survival were significantly affected by deceased donor type, urgent transplantation, and the development of vascular complications. In the multivariate analysis, vascular complications had a negative impact on patient and graft survival, while a longer time from the first AB0i LT in the study showed better results, suggesting an international learning experience. In conclusion, we believe that AB0i LT in children is now a safe procedure that may be adopted more readily in children.
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Boulad, Farid, Arleen D. Auerbach, Nancy A. Kernan, Trudy N. Small, Susan E. Prockop, Sonali Chaudhury, Joanne Castanza, et al. "Fludarabine (Flu) Based Cytoreductive Regimen and T-Cell Depleted Grafts from Unrelated or Mismatched Related Donors for the Treatment of High Risk Patients with Fanconi Anemia (FA)." Blood 104, no. 11 (November 16, 2004): 2152. http://dx.doi.org/10.1182/blood.v104.11.2152.2152.
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Abstract Between 05/98 and 06/04, 15 consecutive patients with FA received hematopoietic stem cell transplants (SCT) from alternative donors at our Center. There were 7 males and 8 females aged 5 to 24 years (median 11.5). Hematologic diagnoses included aplastic anemia (AA) (N=5), myelodysplastic syndrome (MDS) in RAEB (N=4), RAEBT (N=1) or acute myelogenous leukemia (AML) (N=5). High risk features included: Age > 20 years (n=4), prior multiple transfusions (n=11), prior androgen treatment (n=12), prior infections (n=10), or advanced MDS or AML (n=9). Eight pts had related mismatched donors transplants with respective matching at 3/6 (6/10), 4/6 (6/10), 4/6 (7/10) (n=2)), 5/6 (8/10) (n=3) and 5/6 (9/10) HLA-antigens. Seven pts had unrelated donors transplants with respective matching at 5/6 (7/10), 5/6 (8/10) (n=2), 5/6 (9/10) and 6/6 (10/10) (n=3) HLA-antigens. Cytoreduction included single dose total body irradiation (SDTBI) (450 cGy), fludarabine (Flu) (30 mg/m2 x 5) and cyclophosphamide (Cy) (10 mg/Kg x 4). Immunosuppression included rabbit anti-thymocyte globulin (Thymoglobulin) and tacrolimus for all patients. Grafts were G-CSF mobilized CD34+ and E-rosette negative (E-) peripheral blood stem cell transplants for 12 pts and soybean agglutinin negative (SBA-) and E-rosette negative marrow transplants for 3 pts. Cell doses of the grafts were 1.5 – 29.6 x 106 CD34 cells/Kg and 0 – 26 x 103 CD3 cells/Kg. As evidenced by RFLP or FISH, all 15 evaluable pts were fully engrafted and complete chimeras. Fourteen pts were evaluable for graft-versus-host disease (GvHD). GvHD of the skin and of the gut was suspected in two pts but resolved completely prior to immunosuppressive treatment. With a median follow-up of 2.5 years (range 0.2–6), 13 of 15 pts are alive and 11 of 15 are alive disease-free. There were two deaths: one pt died from sepsis/ARDS at 2 months post SCT and one pt from pneumonitis/ARDS and EBV-infection 6 months post SCT. Three pts relapsed (MDS-RAEB x 1 – AML x 2): One pt relapsed 7 months post transplant, received a 2nd transplant from the same donor following busulfan and Flu and is alive, disease-free 18 months post SCT, while the other two pts are awaiting a second SCT. In summary, this cytoreductive regimen used with T-cell depleted stem cell transplants from unrelated or HLA-mismatched related donors for the treatment of high risk patients with Fanconi anemia, results in rapid hematopoietic engraftment and lymphohematopoietic reconstitution with minimal GVHD and a high disease-free survival.
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Cooley, Sarah, Valarie McCullar, Rosanna Wangen, Tracy L. Bergemann, John E. Wagner, Daniel J. Weisdorf, Philip McGlave, and Jeffrey S. Miller. "NK Cell KIR Reconstitution after Allogeneic Hematopoietic Cell Transplant (HCT) Is Affected by T Cell Number and Function." Blood 106, no. 11 (November 16, 2005): 1406. http://dx.doi.org/10.1182/blood.v106.11.1406.1406.
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Abstract NK cell KIR interactions are among the variables known to affect clinical outcomes including relapse, graft versus host disease (GVHD) and survival after HCT. We hypothesized that T cells in graft sources available for HCT may affect KIR recovery and the therapeutic potential of KIR alloreactivity. We studied KIR reconstitution (the percentage of KIR+ NK cells measured by flow cytometry) in blood collected from recipients at day +100 after T cell deplete (TCD-BMT) and unmanipulated (U-BMT) unrelated BM transplants. We found that KIR reconstitution was suppressed compared to the healthy donors, significantly more so after U-BMT transplants (donor: 48.42 ± 2.35% KIR+ NK cells versus recipient: 26.74 ± 1.94, n = 36; P < .001) than after TCD-BMT transplants (donor: 53.34 ± 3.25% versus recipient: 42.68 ± 3.32%, n = 38; P = .017), with P = .001 between the recipient groups. Additionally, multivariate Cox proportional hazards models showed that improved KIR recovery independently correlated with improved survival and that higher NK cell IFN-γ production independently correlated with more frequent acute GVHD in that patient cohort. These data suggested that T cell number in the graft affects KIR reconstitution and transplant outcome. We next examined other sources of hematopoietic cells in which T cell function may be suppressed either by growth factor mobilization (sibling donor unmanipulated peripheral blood: SibU-PB) or the innate naivety of the T cells (umbilical cord blood: UCB). KIR+ NK reconstitution on recovering cells at day +100 after all HCT graft types was significantly less than that on normal donor cells (normals 55.33 ± 1.73%, n = 124; all P < .0006). U-BMT recipients had significantly lower KIR+ NK recovery (27.31 ± 2.06%, n = 36 vs. SibU-PB: 37.58 ± 3.29%, n = 29; TCD-BMT: 42.68 ± 3.32%, n = 38; or UCB, 37.99 ± 2.54%, n = 49) when compared to all other transplant types. The highest absolute T cell inoculum, found in SibU-PB, showed KIR reconstitution similar to that of TCD-BMT, which had the lowest T cell content (p=0.29), perhaps due to the lower alloreactivity of the Sib grafts and to the G-CSF-priming which preferentially mobilizes T cells with a suppressive phenotype. Similarly, KIR reconstitution was better after UCB compared to U-BMT (P = .0027), possibly due to the more permissive interactions with naive T cells. These results suggest that reduced T cell number after T cell depletion, suppressed T cells found after growth factor mobilization, or naive T cells present in UCB grafts enhance in vivo KIR reconstitution after allogeneic HCT when compared to unmanipulated marrow grafts. Such enhanced KIR reconstitution may have clinical consequences. Graft T cells may directly compete for cytokines and growth factors, or may be a surrogate marker for other transplant factors such as the development of GVHD and the requirement for intensive post-transplant immunosuppression. Understanding these interactions will allow judicious selection of hematopoietic cell source to select for enhanced KIR recovery. For example, among unrelated unmanipulated donor grafts, KIR+ NK recovery was significantly better using UCB than adult donors and further investigation may show that this is advantageous to improve clinical outcomes.
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Storb, Rainer F., Richard Champlin, Stanley R. Riddell, Makato Murata, Sophia Bryant, and Edus H. Warren. "Non-Myeloablative Transplants for Malignant Disease." Hematology 2001, no. 1 (January 1, 2001): 375–91. http://dx.doi.org/10.1182/asheducation-2001.1.375.
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Abstract This article discusses changes in the way hematopoietic stem cell allotransplants may be carried out in the future to treat patients with malignant hematological diseases. Specifically, the focus has shifted away from attempts at eradicating underlying diseases through toxic high-dose chemoradiation therapy towards using the stem cell donor's immune cells for that purpose (allogeneic graft-versus-tumor effect). The non-myeloablative transplant approaches hold promise in reducing the morbidity and mortality associated with conventional high-dose chemoradiation therapy, and they allow allogeneic transplants in elderly or medically infirm patients who are at present not candidates for transplantation. In the future, specific graft-versus-tumor responses may become possible by eliciting donor T cell responses to tumor-associated minor histocompatibility antigens. In Section I, Dr. Rainer Storb describes experimental studies in random-bred dogs that rely on non-cytotoxic immunosuppressive agents to establish stable allografts. Powerful postgrafting immunosuppression, traditionally directed at preventing graft-versus-host disease (GVHD), is also used to overcome host-versus-graft (HVG) reactions, thereby dramatically reducing the need for intensive immunosuppressive conditioning programs. Preclinical canine studies have been translated into the clinical setting for treatment of elderly or medically infirm patients with malignant hematological diseases. The pretransplant conditioning has been reduced to a single dose of 2 Gy total body irradiation (TBI) with or without fludarabine. The lack of toxicity makes it possible for transplants to be conducted in the outpatient setting. Multicenter trials have been initiated, and more than 300 patients have been successfully treated with hematopoietic stem cell grafts both from related and unrelated HLA-matched donors. In Section II, Dr. Richard Champlin describes clinical studies with therapeutic strategies that utilize relatively non-toxic, nonmyeloablative disease-specific preparative regimens incorporating fludarabine, together with other chemotherapeutic agents, to achieve disease suppression and engraftment of allogeneic hematopoietic cells and to allow subsequent infusions of donor lymphocytes. Remissions have been seen in patients with acute myelocytic, chronic myelocytic, chronic lymphocytic, leukemias, lymphomas, and myelomas. In Section III, Dr. Stanley Riddell and colleagues describe studies on isolation of T cells reactive with minor histocompatibility (H) antigens and involved both in GVHD and graft-versus-leukemia (GVL) responses. For example, the gene encoding a novel H-Y antigen in humans has been identified and shown to exhibit restricted tissue expression. Acute myelocytic leukemia stem cells were demonstrated to express the H-Y antigen and additional minor H antigens, and engraftment of such cells in NOD/SCID mice could be selectively prevented by minor antigen-specific T-cell clones. An autosomal encoded human minor H antigen associated with chronic GVHD has been demonstrated. A trial evaluating therapy of relapsed acute myelocytic leukemia or acute lymphoblastic leukemia after allogeneic stem cell transplantation with T-cell clones specific for recipient minor H antigens has been initiated.
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Bellini, Maria Irene, Aisling E. Courtney, and Jennifer A. McCaughan. "Living Donor Kidney Transplantation Improves Graft and Recipient Survival in Patients with Multiple Kidney Transplants." Journal of Clinical Medicine 9, no. 7 (July 5, 2020): 2118. http://dx.doi.org/10.3390/jcm9072118.
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Background: Failed kidney transplant recipients benefit from a new graft as the general incident dialysis population, although additional challenges in the management of these patients are often limiting the long-term outcomes. Previously failed grafts, a long history of comorbidities, side effects of long-term immunosuppression and previous surgical interventions are common characteristics in the repeated kidney transplantation population, leading to significant complex immunological and technical aspects and often compromising the short- and long-term results. Although recipients’ factors are acknowledged to represent one of the main determinants for graft and patient survival, there is increasing interest in expanding the donor’s pool safely, particularly for high-risk candidates. The role of living kidney donation in this peculiar context of repeated kidney transplantation has not been assessed thoroughly. The aim of the present study is to analyse the effects of a high-quality graft, such as the one retrieved from living kidney donors, in the repeated kidney transplant population context. Methods: Retrospective analysis of the outcomes of the repeated kidney transplant population at our institution from 1968 to 2019. Data were extracted from a prospectively maintained database and stratified according to the number of transplants: 1st, 2nd or 3rd+. The main outcomes were graft and patient survivals, recorded from time of transplant to graft failure (return to dialysis) and censored at patient death with a functioning graft. Duration of renal replacement therapy was expressed as cumulative time per month. A multivariate analysis considering death-censored graft survival, decade of transplantation, recipient age, donor age, living donor, transplant number, ischaemic time, time on renal replacement therapy prior to transplant and HLA mismatch at HLA-A, -B and -DR was conducted. In the multivariate analysis of recipient survival, diabetic nephropathy as primary renal disease was also included. Results: A total of 2395 kidney transplant recipients were analysed: 2062 (83.8%) with the 1st kidney transplant, 279 (11.3%) with the 2nd graft, 46 (2.2%) with the 3rd+. Mean age of 1st kidney transplant recipients was 43.6 ± 16.3 years, versus 39.9 ± 14.4 for 2nd and 41.4 ± 11.5 for 3rd+ (p < 0.001). Aside from being younger, repeated kidney transplant patients were also more often males (p = 0.006), with a longer time spent on renal replacement therapy (p < 0.0001) and a higher degree of sensitisation, expressed as calculated reaction frequency (p < 0.001). There was also an association between multiple kidney transplants and better HLA match at transplantation (p < 0.0001). A difference in death-censored graft survival by number of transplants was seen, with a median graft survival of 328 months for recipients of the 1st transplant, 209 months for the 2nd and 150 months for the 3rd+ (p = 0.038). The same difference was seen in deceased donor kidneys (p = 0.048), but not in grafts from living donors (p = 0.2). Patient survival was comparable between the three groups (p = 0.59). Conclusions: In the attempt to expand the organ donor pool, particular attention should be reserved to high complex recipients, such as the repeated kidney transplant population. In this peculiar context, the quality of the donor has been shown to represent a main determinant for graft survival—in fact, kidney retrieved from living donors provide comparable outcomes to those from single-graft recipients.
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Weisdorf, Daniel J., Mary Eapen, Annalisa Ruggeri, Mei-Jie Zhang, Xiaobo Zhong, Claudio Brunstein, Celalettin Ustun, Vanderson Rocha, and Eliane Gluckman. "Alternative Donor Hematopoietic Transplantation For Patients Older Than 50 Years With AML In First Complete Remission: Unrelated Donor and Umbilical Cord Blood Transplantation Outcomes." Blood 122, no. 21 (November 15, 2013): 302. http://dx.doi.org/10.1182/blood.v122.21.302.302.
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Abstract Post-remission allogeneic transplantation is increasingly used for treatment of the high-risk acute myeloid leukemia (AML) affecting older adults. We analyzed 740 adults over age 50 with AML in first complete remission (CR1) to compare the effectiveness of volunteer unrelated donor (URD) and umbilical cord blood (UCB) graft sources in providing a successful transplant. For prospective cases reported (2005-2010) to the Center for International Blood and Marrow Transplant Research and Eurocord, we evaluated 8/8 HLA allele matched (at HLA-A, -B, -C, -DRB1) n=441; 7/8 matched URD n=94 and UCB n=205 for the outcomes of engraftment, treatment related (non-relapse) mortality (TRM), relapse, leukemia free survival (LFS) and overall survival (OS) using the cumulative incidence and Kaplan-Meier estimators and multivariate Cox regression modeling. Patient age (median 58, range 50-75), gender and CMV serostatus were similar across the treatment groups. However, UCB recipients were less likely to achieve CR within 8 weeks, more likely to report Intermediate and unfavorable risk cytogenetics, more likely to receive reduced-intensity conditioning compared to myeloablative conditioning regimens, and receive cyclosporin rather than tacrolimus-based GVHD prophylaxis. After a median follow-up of 50, 61 and 37 months in 8/8 URD, 7/8 URD and UCB grafts, neutrophil and platelet recovery was slower in UCB compared to URD recipients; the day-42 incidence of neutrophil recovery in UCB recipients was 85% compared to 98% and 92% in 8/8 and 7/8 URD recipients. While there were no significant differences in rates of grade II to IV acute GVHD (35%, 36% and 44% in UCB, 8/8 URD and 7/8 URD recipients respectively), the 3-year incidence of chronic GVHD was significantly lower in UCB recipients (28% compared to 53% and 59% in 8/8 and 7/8 URD recipients. Compared to 8/8 URD transplants, multivariate analysis confirmed higher TRM after transplantation of UCB grafts, but only in the first 3 months (HR 2.83, p<0.0001) with similar risks thereafter (HR 1.00, p=0.99). Compared to 8/8 URD transplants, TRM was higher after 7/8 URD transplants (HR 1.73, p=0.005). There were no significant differences in relapse risks between the three groups; compared to 8/8 URD transplants, relapse risks after UCB and 7/8 URD transplants were HR 1.15, p=0.36 and HR 0.86, p=0.47, respectively. These hazards yielded higher adjusted 3-year LFS after 8/8 URD (39% [95% CI 34%-43%]) compared to 7/8 URD (34% [95% CI 24%-43%]) and UCB transplants (28% [95% CI 22%-35%]), p=0.015) and adjusted 3-year OS of 43% (95% CI 38%-48%), 37% (95% CI 27%-46%) and 30% (95% CI 23%-37%), respectively (p=0.003). Relapse risks were greater in patients with intermediate or unfavorable risk cytogenetics, independent of graft type and leukemia-free and overall survival were also worse in patients with unfavorable risk cytogenetics and in patients over age 60. For the older population with AML, allotransplantation in CR1 can provide extended leukemia-free survival for 30%-43% of patients using any of these graft sources. While 8/8 URD transplants are preferred for patients who can promptly obtain a well-matched URD, for ethnic or racial minorities, UCB grafts provide a meaningful chance of extended LFS, even though nearly all UCB grafts are HLA mismatched. Additionally, the rapid availability of UCB provides effective therapy for older patients with expected short initial remissions: settings where ongoing consolidation therapy has not been effective in limiting risks of relapse. Later TRM and relapse rates were similar, lower risks of chronic GVHD and the need for long-term immunosuppression and its morbidities may be of particular value for these older patients. These encouraging results suggest that allotransplantation need not be withheld from older patients and for clinically suitable AML patients, can produce extended and even curative long-term survival. Disclosures: Gluckman Cord use: Honoraria; gamida: Honoraria.
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Horwitz, Mitchell, John Chute, Cristina Gasparetto, Gwynn Long, David Rizzieri, Ashley Morris, Jackie McPherson, Keith Sullivan, and Nelson Chao. "Myeloablative Intravenous Busulfan/Fludarabine Conditioning Does Not Facilitate Reliable Engraftment of Dual Umbilical Cord Blood Grafts in Adult Recipients." Blood 110, no. 11 (November 16, 2007): 2007. http://dx.doi.org/10.1182/blood.v110.11.2007.2007.
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Abstract Bone marrow conditioning with the combination of myeloablative doses of intravenous busulfan (IVBu) with fludarabine (Flu) has gained wide acceptance as a viable alternative to the conventional busulfan and cyclophosphamide combination. When followed by transplantation with peripheral blood stem cells from matched related or unrelated donors, IVBu/Flu facilitates reliable engraftment with reduced toxicity (Blood. 2004;104:857). Whether this combination provides sufficient immunosuppression to facilitate engraftment of partially matched umbilical cord blood (UCB) grafts has yet to be reported. Ten patients with median age of 41 years (range 21–54 years) were enrolled in an IRB approved clinical trial with a primary endpoint to assess donor engraftment. Stopping rules were constructed to prevent graft failure from exceeding 20%. Disease characteristics include AML; CR1-1pt, CR2-3pts, MDS-4pts, CML-2pts. Seven of 10 patients had high-risk cytogenetic abnormalities. Conditioning consisted of fludarabine 40mg/m2 daily × 4 days and intravenous busulfan 130mg/m2 once daily × 4 days. Six patients received the drugs sequentially, and 4 concurrently. GvHD prophylaxis was provided by tacrolimus and mycophenolate mofetil. The cord blood grafts were at least 4 of 6 HLA-matched with the recipient and 3 of 6 HLA matched between grafts (low resolution class I, high resolution class II). The median combined cryopreserved total nucleated cell dose was 3.5 × 107/kg recipient body weight (range 2.1 to 4.4 × 107/kg). Engraftment of one or both UCB grafts was detected in only 4 of 10 recipients resulting in premature closure of the study as per graft failure stopping rules. None of the patients with donor engraftment achieved full donor chimerism and all ultimately died of relapsed disease. Of the 6 patients that experienced primary graft failure, 5 underwent second transplants (1 autologous, 4 haploidentical). One haploidentical and one autologous graft recipient remain alive and disease free 18 months and 13 months post transplant, respectively. In summary, 5 of 10 patients died of relapsed disease and 3 patients from treatment-related toxicity. Busulfan pharmacokinetic measurements were performed on the first and fourth dose. Interdose PK variability between day 1 and 4 was less than 15%. The mean and median AUCs were 4181 and 4195 μmol-min, respectively (range, 2634–5279 μmol-min). These levels are comparable to what has been previously reported for once daily IVBu dosing. We conclude that the myeloablative conditioning regimen of once daily IVBu with Flu provides insufficient immunosuppression to allow for engraftment of a partially matched umbilical cord blood graft.
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Boulad, Farid, Ann Jakubowski, Esperanza Papadopoulos, Katharine C. Hsu, Miguel Angel Perales, Marcel van den Brink, James W. Young, et al. "Phase II Trial of a Chemotherapy-Only Regimen of Busulfan, Melphalan, Fludarabine and R-ATG Followed by Allogeneic T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplants (HSCT) for the Treatment of Myeloid Malignancies." Blood 110, no. 11 (November 16, 2007): 2991. http://dx.doi.org/10.1182/blood.v110.11.2991.2991.
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Abstract In this trial, we wished to test whether a chemotherapeutic regimen combining myeloablation with busulfan (Bu) and melphalan (Mel) with fludarabine (Flu) and ATG could be used to secure consistent engraftment of T-cell depleted transplants thereby reducing GvHD and regimen-related toxicity without increasing risk of relapse in patients with advanced myeloid malignancies. Between 08/01 and 06/07, sixty two patients with a diagnosis of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) were enrolled on this trial, including 33 males and 29 females of a median age of 54.5 years (range 0.6–71.3 years). Eleven patients had primary AML in CR1 (N=4) or ≥ CR2 (N=7). Thirty two pts had primary (1°) MDS and 19 pts treatment related (2°) MDS/AML. Forty five of the 51 pts with 1° or 2° MDS had ≥ RAEB status at diagnosis and required chemotherapy prior to transplant. The status of MDS pts at the time of SCT included: CR1 (N=14), CR2 (N=3), primary RA (N=6), second RA (N=21), > RA (N=7). Thirteen pts received allografts from HLA-matched related donors, 4 pts from HLA-mismatched related donors, 22 pts from HLA-matched unrelated donors, and 23 pts from HLA-mismatched unrelated donors. Cytoreduction consisted of BU (0.8–1 mg/Kg/dose × 10 doses), MEL (70 mg/Kg/day × 2) and FLU (25 mg/m2/day × 5). Graft rejection prophylaxis included pre-transplant rabbit ATG (Thymoglobulin) (2.5 mg/Kg/day × 2) and no post transplant immunosuppression was administered. Fifty nine pts received G-CSF mobilized peripheral blood stem cell transplants (PBSCT) that were T-cell depleted by positive CD34 selection and sheep-RBC rosetting while three pts received soybean agglutinin E-rosette depleted marrow grafts. For the PBSCT grafts, the median CD34+ cell dose/Kg was 5.0 × 106 (range: 1.3–28.8 × 106) and the median CD3+ cell dose/Kg was 1.1 × 103 (range 0–12 × 103). Median follow-up was 16 months (range 0.7–68.7 mo). Engraftment occurred in 59 of 61 evaluable pts, but two recipients of unrelated donor grafts suffered a graft failure. Acute grade 2–4 GvHD occurred in 7 pts, and chronic GvHD in three of 40 evaluable pts. Twenty two pts died of infection (n=7), organ toxicity (n=6), GvHD (n=3), graft failure (n=1) or relapse (n=5). The two-year probabilities of overall survival (OS) and disease-free survival (DFS) for the entire patient cohort were 62% and 54% respectively with a two-year probability of relapse of 16.2%.The two-year DFS for recipients of HLA-matched related and unrelated grafts was 54% and 57% for recipients of HLA-disparate unrelated grafts. Two-year DFS was 58% for pts with primary AML, 57% for pts with primary MDS and 51% for pts with secondary MDS/AML. Two-year DFS was 60.6% for pts ≤ 50 years and 49.7% for pts > 50 years. In summary, cytoreduction with Bu Mel and Flu and rabbit ATG has secured consistent engraftment of T-cell depleted transplants for both HLA-matched or disparate, related and unrelated donors. The incidence of acute or chronic GvHD and disease relapse were low, with favorable outcomes in this cohort of older patients with high risk myeloid malignancies.
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Aversa, F., A. Tabilio, A. Terenzi, A. Velardi, F. Falzetti, C. Giannoni, R. Iacucci, T. Zei, MP Martelli, and C. Gambelunghe. "Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum." Blood 84, no. 11 (December 1, 1994): 3948–55. http://dx.doi.org/10.1182/blood.v84.11.3948.bloodjournal84113948.
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Patients who undergo transplantation with haploidentical “three-loci” mismatched T-cell-depleted bone marrow (BM) are at high risk for graft failure. To overcome the host-versus-graft barrier, we increased the size of the graft inoculum, which has been shown to be a major factor in controlling both immune rejection and stem cell competition in murine models. Seventeen patients (mean age, 23.2 years; range, 6 to 51 years) with end-stage chemoresistant leukemia were received transplants of a combination of BM with recombinant human granulocyte colony- stimulating factor-mobilized peripheral blood progenitor cells from HLA- haploidentical “three-loci” incompatible family members. The average concentration of colony-forming unit-granulocyte-macrophage in the final inoculum was sevenfold to 10-fold greater than that found in BM alone. The sole graft-versus-host disease (GVHD) prophylaxis consisted of T-cell depletion of the graft by the soybean agglutination and E- rosetting technique. The conditioning regimen included total body irradiation in a single fraction at a fast dose rate, antithymocyte globulin, cyclophosphamide and thiotepa to provide both immunosuppression and myeloablation. One patient rejected the graft and the other 16 had early and sustained full donor-type engraftment. One patient who received a much greater quantity of T lymphocytes than any other patient died from grade IV acute GVHD. There were no other cases of GVHD > or = grade II. Nine patients died from transplant-related toxicity, 2 relapsed, and 6 patients are alive and event-free at a median follow-up of 230 days (range, 100 to 485 days). Our results show that a highly immunosuppressive and myeloablative conditioning followed by transplantation of a large number of stem cells depleted of T lymphocytes by soybean agglutination and E-rosetting technique has made transplantation of three HLA-antigen disparate grafts possible, with only rare cases of GVHD.
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Hau, Scott, Bronagh Clarke, Caroline Thaung, and Daniel F. P. Larkin. "Longitudinal changes in corneal leucocyte density in vivo following transplantation." British Journal of Ophthalmology 103, no. 8 (October 24, 2018): 1035–41. http://dx.doi.org/10.1136/bjophthalmol-2018-312386.
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AimsTo prospectively evaluate the changes in corneal leucocyte density with in vivo confocal microscopy (IVCM) following transplantation and to determine if leucocyte density post-transplant is an indicator of graft rejection risk.MethodsIVCM imaging of cornea pre-transplant and post-transplant at 1 week, 1, 3 and 12 months. The changes in leucocyte density associated with diagnosis, vascularisation, type of keratoplasty, topical steroid and immunosuppression treatment, allograft rejection and failure within 4 years post-transplant were analysed.ResultsSub-basal nerve plexus total central leucocyte density (SBNP-TCLD) varied with diagnosis (p<0.001), interval post-transplant (p<0.001), degree of vascularisation (p=0.001) and rejection episodes in eyes off topical steroid (p=0.01). The highest SBNP-TCLD was found in eyes with inflammation pre-transplant. Mean 12-month SBNP-TCLD in eyes which had rejection episodes was almost double that in eyes which did not (79.0 and 39.8 cells/mm2, respectively). SBNP-TCLD >63.5 cells/mm2 was associated with a higher risk of rejection within 1 year (p=0.04) and 4 years (p=0.007). Changes in leucocyte density on the donor endothelium significantly differed between penetrating keratoplasty and deep anterior lamellar keratoplasty grafts (p<0.01) and in those in which rejection episodes were observed (p<0.001).ConclusionsLeucocyte density varies with corneal diagnosis, extent of vascularisation and interval post-transplant. Topical steroid treatment is associated with reduced leucocyte density and risk of graft rejection. Higher endothelium leucocyte density correlates significantly with previous or subsequent rejection episodes. Leucocyte density measurement by IVCM may be useful in identifying transplants at risk of rejection.
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Storb, R., M. Pepe, C. Anasetti, FR Appelbaum, P. Beatty, K. Doney, P. Martin, P. Stewart, KM Sullivan, and R. Witherspoon. "What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants?" Blood 76, no. 5 (September 1, 1990): 1037–45. http://dx.doi.org/10.1182/blood.v76.5.1037.1037.
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Abstract One hundred forty-seven consecutive patients with leukemia, myelodysplastic syndrome, or aplastic anemia were treated by marrow grafts from genotypically HLA-identical siblings (n = 122) or HLA- haploidentical family members (n = 25). Haploidentical recipients differed from their donors for no more than one HLA locus on the nonshared haplotype. All were given postgrafting immunosuppression with a combination of methotrexate and cyclosporine. In a randomized study we explored whether prednisone administered from day 0 through 35 along with methotrexate/cyclosporine could improve prevention of acute graft- versus-host disease (GVHD). The GVHD incidence in patients not given prednisone was comparable with that previously reported with methotrexate/cyclosporine. Unexpectedly, significant increases in acute and also chronic GVHD were seen in HLA-identical recipients administered prednisone, but not in the small number of patients administered HLA-nonidentical grafts. However, the resultant increase in transplant-related mortality in patients administered prednisone was offset by an increase in leukemic relapse in patients not administered prednisone, presumably related to the absence of a graft-versus- leukemia effect. Therefore, overall disease-free survival of the two groups of patients was comparable, with slightly more than 50% of the patients being alive at more than 2 years after transplantation. We speculated that prednisone adversely affected GVHD prophylaxis, interfering with methotrexate's cell cycle-dependent suppression of donor lymphocyte proliferation in response to host antigens. In a pilot study we explored whether beginning prednisone on day 15, after completion of methotrexate administration, would avoid this adverse effect. The GVHD incidence in patients administered methotrexate/cyclosporine along with “late” prednisone was comparable with that in patients not administered prednisone. We conclude that methotrexate/cyclosporine is effective in decreasing the incidence of grade II through IV GVHD, and that the addition of prednisone to this regimen is not beneficial in recipients of HLA-identical marrow grafts.
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Storb, R., M. Pepe, C. Anasetti, FR Appelbaum, P. Beatty, K. Doney, P. Martin, P. Stewart, KM Sullivan, and R. Witherspoon. "What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants?" Blood 76, no. 5 (September 1, 1990): 1037–45. http://dx.doi.org/10.1182/blood.v76.5.1037.bloodjournal7651037.
Full textAbstract:
One hundred forty-seven consecutive patients with leukemia, myelodysplastic syndrome, or aplastic anemia were treated by marrow grafts from genotypically HLA-identical siblings (n = 122) or HLA- haploidentical family members (n = 25). Haploidentical recipients differed from their donors for no more than one HLA locus on the nonshared haplotype. All were given postgrafting immunosuppression with a combination of methotrexate and cyclosporine. In a randomized study we explored whether prednisone administered from day 0 through 35 along with methotrexate/cyclosporine could improve prevention of acute graft- versus-host disease (GVHD). The GVHD incidence in patients not given prednisone was comparable with that previously reported with methotrexate/cyclosporine. Unexpectedly, significant increases in acute and also chronic GVHD were seen in HLA-identical recipients administered prednisone, but not in the small number of patients administered HLA-nonidentical grafts. However, the resultant increase in transplant-related mortality in patients administered prednisone was offset by an increase in leukemic relapse in patients not administered prednisone, presumably related to the absence of a graft-versus- leukemia effect. Therefore, overall disease-free survival of the two groups of patients was comparable, with slightly more than 50% of the patients being alive at more than 2 years after transplantation. We speculated that prednisone adversely affected GVHD prophylaxis, interfering with methotrexate's cell cycle-dependent suppression of donor lymphocyte proliferation in response to host antigens. In a pilot study we explored whether beginning prednisone on day 15, after completion of methotrexate administration, would avoid this adverse effect. The GVHD incidence in patients administered methotrexate/cyclosporine along with “late” prednisone was comparable with that in patients not administered prednisone. We conclude that methotrexate/cyclosporine is effective in decreasing the incidence of grade II through IV GVHD, and that the addition of prednisone to this regimen is not beneficial in recipients of HLA-identical marrow grafts.
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Calne, Roy. "Clinical transplantation: current problems, possible solutions." Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1461 (August 18, 2005): 1797–801. http://dx.doi.org/10.1098/rstb.2005.1708.
Full textAbstract:
I have attempted to summarize the progress that has been made in organ transplantation in the past 50 years since the first identical twin transplant. For those who have worked long in this area its success has been remarkable. We currently expect patients to survive the operation and more than 90% of the graft to be functioning at a year with the half-life of the graft beyond 10 years, with some patients surviving into the fifth decade after kidney transplantation with grafts from unrelated donors and the fourth decade for liver transplants. Now the main stumbling block is shortage of organ donors and this is unlikely to be solved easily. There has been a considerable increase in donations from living volunteers and also the worry of immoral and illegal practices. In the future, we can expect considerable advances in immunosuppression with more effective, less toxic drugs and in some patients induction therapy that may approach tolerance so that no maintenance therapy will eventually be needed. Cell transplantation is likely to be developed as treatment for the clinic in the next 5–10 years, but developments of transplantation from animal to man still remains unsolved and unlikely to be successful in the clinic in the near future.
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Heeckt, P. F., W. Halfter, W. H. Schraut, and A. J. Bauer. "Chronic rejection causes early destruction of the intrinsic nervous system in rat intestinal transplants." American Journal of Physiology-Gastrointestinal and Liver Physiology 273, no. 2 (August 1, 1997): G413—G421. http://dx.doi.org/10.1152/ajpgi.1997.273.2.g413.
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Chronic rejection is the major cause of late intestinal allograft dysfunction. We have previously shown that chronic rejection alters the muscularis externa of the graft. This study determined structural and functional changes to the enteric nerves during chronic rejection. Chronic rejection was achieved in orthotopic intestinal transplants (ACI to Lewis) by limited immunosuppression. Syngeneic transplants (ACI to ACI) and unoperated ACI rats served as controls. Animals were clinically healthy and showed no significant alterations in the mucosal architecture on postoperative day 90. Staining for NADPH diaphorase activity (nitric oxide synthase-containing neurons) and with neurofilament antibody RT-97 revealed that chronic rejection decreased the number of jejunal myenteric ganglia by approximately 50%. Inhibitory junction potentials (IJPs) to circular muscle cells were determined by electrical field stimulation (EFS). In controls and syngeneic grafts, EFS caused a stimulus-dependent increase in IJP amplitude, with a maximal amplitude of 9 +/- 0.4 and 10 +/- 0.8 mV, respectively. Chronic rejection in allografts markedly increased the threshold for IJP initiation and decreased the maximal IJP amplitude (5 +/- 0.8 mV). Our data indicate that chronic rejection severely damages the muscularis and the enteric nervous system before mucosal changes become evident.
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Thakar, Monica S., Ted A. Gooley, Erlinda B. Santos, Rainer F. Storb, and Brenda M. Sandmaier. "High-Dose Methotrexate (MTX) as Part of a Novel Immunosuppressive Regimen in Canine MHC-Haploidentical Hematopoietic Cell Transplantation (HCT)." Blood 108, no. 11 (November 16, 2006): 3180. http://dx.doi.org/10.1182/blood.v108.11.3180.3180.
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Abstract In a preclinical canine model using major histocompatibility (MHC)-haploidentical littermate peripheral blood stem cell (PBSC) grafts, initial donor chimerism could be achieved after a nonmyeloablative conditioning regimen consisting of monoclonal antibody S5 (anti-CD44) from days −7 to −2, 200 cGy TBI on day 0, and MMF and cyclosporine for postgrafting immunosuppression. However, sustainable donor chimerisms could not be achieved in many of these dogs, with 25 of 44 (57%) rejecting their grafts at a median of 7 weeks after transplant. In order to improve the engraftment rate, a novel strategy to overcome the immunological barrier created by this MHC-haploidentical setting was developed. By adding single, progressively higher doses of MTX on day+3 after transplantation to the above regimen, we hoped to control host T and NK cells, both of which contribute to graft rejection in MHC-haploidentical HCT, and to target alloreactive donor T cells which are responsible for graft-versus-host disease (GVHD). Once dose toxicity is established, this system will also allow the study of transplants using gene-modified, MTX-resistant CD34 selected PBSC, which can provide additional intrinsic graft protection on exposure to MTX. To date, 11 dogs have been transplanted using the above regimen and adding either 50 (n=5), 100 (n=3), or 200 (n=3) mg/m2 MTX on day +3 followed by leucovorin rescue on days +4 and +5. Early results showed that 4 of 5 dogs experienced graft rejection in the MTX50 group, 0 of 3 dogs rejected in MTX100 (p=0.047, Monte Carlo), and all 3 dogs in MTX200 have continued to exhibit stable mixed chimerisms from +42 to +76 days after transplant. Dogs in all 3 cohorts had rapid engraftment within 1 week, with similar average peak mononuclear cell (MNC) chimerisms at comparable timepoints (83% at 5 wks, 88% at 6 wks, and 80% at 5 wks at MTX50, 100, and 200 respectively). None of the 11 dogs have shown evidence of GVHD or MTX toxicity, and all dogs cleared MTX within 48 hours. All dogs exhibited early donor tolerance on mixed lymphocyte culture assays within 2 weeks and preserved NK activity posttransplant. While these data are preliminary, adding single, progressively larger doses of MTX on day +3 to a novel, nonmyeloablative conditioning regimen appeared to improve engraftment among MHC-haploidentical canine recipients with no signs of GVHD. There was high initial donor chimerism without undue early toxicity. Further, this study will aid in our establishment of high-dose, posttransplant MTX as a way of promoting sustained donor chimerism after transplanting CD34 selected, MTX-resistant canine PBSC in the MHC-haploidentical setting. This preclinical data serve as a basis for developing nonmyeloablative transplant options for patients without HLA-identical donors.
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Martin, PJ, JA Hansen, CD Buckner, JE Sanders, HJ Deeg, P. Stewart, FR Appelbaum, R. Clift, A. Fefer, and RP Witherspoon. "Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts." Blood 66, no. 3 (September 1, 1985): 664–72. http://dx.doi.org/10.1182/blood.v66.3.664.664.
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Abstract We report results of a pilot study designed to evaluate the effects of in vitro depletion of T lymphocytes from donor marrow in patients receiving HLA-identical marrow grafts for treatment of hematologic malignancies. Twenty patients aged 31 to 50 years were prepared for transplantation with cyclophosphamide (120 mg/kg) and fractionated total body irradiation (12.0 or 15.75 Gy). All received cyclosporine after grafting. The donor marrows were treated with a mixture of eight murine monoclonal antibodies and rabbit serum complement in a manner that achieved a 2- to 3-log depletion of T cells in most patients. Initial engraftment occurred promptly in 19 of the patients, and only three had clinically significant acute graft-versus-host disease. Depletion of donor T cells, however, was associated with an increased incidence of graft failure, which occurred as late as 244 days after transplantation. Graft failure was transient in one patient but apparently was irreversible in seven others. Three of the seven patients had cytogenetic but not morphological evidence of leukemic relapse at the time of graft failure. All seven patients with irreversible graft failure have died, six after receiving second bone marrow transplants. Seven of the eight cases of graft failure occurred among the 11 patients prepared for transplantation with 12.0 Gy of total-body irradiation, and only one occurred among the nine patients with advanced malignancies who received 15.75 Gy of total-body irradiation. This association with irradiation dose suggests that host factors were partly responsible for the graft failures. Because graft failure seldom occurs in irradiated recipients of unmodified HLA- identical allogeneic marrow transplants, it appears that T cells in the donor marrow may serve a beneficial function in helping to maintain sustained engraftment possibly by eliminating host cells that can cause graft failure. Optimal application of in vitro manipulation of donor marrow as a method for preventing graft-versus-host disease will require more effective immunosuppression of the recipient in order to assure sustained engraftment and function of donor stem cells.
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Martin, PJ, JA Hansen, CD Buckner, JE Sanders, HJ Deeg, P. Stewart, FR Appelbaum, R. Clift, A. Fefer, and RP Witherspoon. "Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts." Blood 66, no. 3 (September 1, 1985): 664–72. http://dx.doi.org/10.1182/blood.v66.3.664.bloodjournal663664.
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We report results of a pilot study designed to evaluate the effects of in vitro depletion of T lymphocytes from donor marrow in patients receiving HLA-identical marrow grafts for treatment of hematologic malignancies. Twenty patients aged 31 to 50 years were prepared for transplantation with cyclophosphamide (120 mg/kg) and fractionated total body irradiation (12.0 or 15.75 Gy). All received cyclosporine after grafting. The donor marrows were treated with a mixture of eight murine monoclonal antibodies and rabbit serum complement in a manner that achieved a 2- to 3-log depletion of T cells in most patients. Initial engraftment occurred promptly in 19 of the patients, and only three had clinically significant acute graft-versus-host disease. Depletion of donor T cells, however, was associated with an increased incidence of graft failure, which occurred as late as 244 days after transplantation. Graft failure was transient in one patient but apparently was irreversible in seven others. Three of the seven patients had cytogenetic but not morphological evidence of leukemic relapse at the time of graft failure. All seven patients with irreversible graft failure have died, six after receiving second bone marrow transplants. Seven of the eight cases of graft failure occurred among the 11 patients prepared for transplantation with 12.0 Gy of total-body irradiation, and only one occurred among the nine patients with advanced malignancies who received 15.75 Gy of total-body irradiation. This association with irradiation dose suggests that host factors were partly responsible for the graft failures. Because graft failure seldom occurs in irradiated recipients of unmodified HLA- identical allogeneic marrow transplants, it appears that T cells in the donor marrow may serve a beneficial function in helping to maintain sustained engraftment possibly by eliminating host cells that can cause graft failure. Optimal application of in vitro manipulation of donor marrow as a method for preventing graft-versus-host disease will require more effective immunosuppression of the recipient in order to assure sustained engraftment and function of donor stem cells.
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Hering, B. J., C. C. Browatzki, A. Schultz, R. G. Bretzel, and K. F. Federlin. "Clinical Islet Transplantation — Registry Report, Accomplishments in the past and Future Research Needs." Cell Transplantation 2, no. 4 (July 1993): 269–82. http://dx.doi.org/10.1177/096368979300200403.
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This review provides the results of a recent analysis of the Islet Transplant Registry on clinical adult islet transplants performed worldwide through June 30, 1992. Between December 12, 1893 and June 30, 1992, 167 adult islet transplants were performed at 25 institutions worldwide, including 104 at 9 institutions in North America, 62 at 15 institutions in Europe, and 1 elsewhere. The total number of diabetic patients reported to be insulin independent after adult islet allotransplantation through June 30,1992, was 19. In an analysis by era, the percentage of patients that showed positive basal C-peptide levels (i.e. ≥ 1 ng/mL at ≥ 1 mo) posttransplant, and that became insulin independent (>1 wk) in the 1985-1989 era (n = 35 cases) were 20% and 6%, and in the 1990-1992 era (n = 69 cases) were 64% and 20%, respectively, and thus have improved significantly (p < 0.001 and p < 0.05). For the 1990-1992 period, the percentage of patients who showed positive basal C-peptide levels post-transplant, and who became insulin independent in the single donor pancreas group (n = 31 cases) were 52% and 13%, and in the multiple donor pancreata group (n = 36 cases) were 75% and 28%, respectively. Islet graft function rates were nearly identical for grafts prepared from pancreata stored ≤6 h (n = 27) and >6 ≤ 12 h (n = 29), so that 67% and 72% showed positive basal C-peptide levels, and 30% and 21% of the recipients became insulin independent, respectively. No single patient showed islet graft function sufficient to allow withdrawal from insulin, if the pancreata have been stored for more than 12 h. In regard to recipient category for the six groups, namely IAK (islet after kidney), SIK (simultaneous islet kidney transplantation), SIL (simultaneous islet liver transplantation), SIL(C) (simultaneous islet liver transplantation after cluster operation), SIKL (simultaneous islet kidney liver transplantation), and SIH-L (simultaneous islet heart-lung transplantation), the number of patients who showed positive basal C-peptide levels post-transplant was 11 (58%), 17 (57%), 5 (83%), 8 (80%), 1 (50%), and 0 (0%), and the number of insulin independent patients was 4 (21%), 4 (13%), 0 (0%), 6 (60%), 0 (0%), and 0 (0%), respectively. Comparing the two largest recipient categories, namely IAK and SIK, no difference in the outcome of these transplants was apparent. The only sites of transplantation in the period between 1990-1992 were the liver, epiploic flap, and spleen, with the total number of recipients being 60 (90%), 4 (6%), and 3 (4%), respectively. For these three groups, the number of patients who showed positive basal C-peptide levels was 38 (63%), 2 (50%), and 1 (33%), and the number of insulin independent patients was 13 (22%), 0 (0%) and 0 (0%), respectively. In the overwhelming majority of cases, recipient selection was not based on prospective HLA donor/recipient matching. In different categories of HLA mismatching (i.e., AB-, DR-, BDR-, and ABDR-mismatch) no obvious tendency or difference in outcome could be demonstrated. In the 1990-1992 period, 16 patients (24%) received OKT3, 26 patients (39%) received ALS, ALG, or ATG, and 25 patients (37%) received neither monoclonal nor polyclonal T-cell antibodies for induction immunosuppression. For the three groups mentioned, the number of patients who showed positive basal C-peptide levels was 12 (86%), 16 (62%), and 15 (60%), and the number of insulin independent patients was 2 (14%), 6 (23%), and 6 (24%), respectively. A synopsis of all pretransplant C-peptide-negative Type I diabetic patients who succeeded in insulin independence revealed certain common characteristics, such as transplantations of ≥8000 islet equivalents per kilogram body weight, a purity of transplanted islets ≥ 50% (in all but one case), the liver as implantation site, and OKT3 or ALG/ ALS/ATG for induction immunosuppression (“state of the art” cases). Because it has been unequivocally proven that islet transplantation can be performed successfully in association with other organ transplants, more attention should be drawn to the nonuremic, nonkidney Type I diabetic patients, who have not been reported in a single case since 1990. This is the real target group, that could benefit most from islet replacement. However, islet transplantation in this recipient category will only have an undisputable indication, if low-risk, but effective methods other than life-long immunosuppression to protect the islet graft from rejection can be developed.
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Shasheleva, Daria, Larisa Shelikhova, Zhanna Shekhovtsova, Dmitriy Balashov, Pavel Trakhtman, Elena Boyakova, Elena Raykina, et al. "Transplantation from Matched Unrelated and Haploidentical Donor in Pediatric Severe Aplastic Anemia: Experience with TCR Alpha/Beta and CD19 Depletion As Graft Processing Method." Blood 128, no. 22 (December 2, 2016): 2294. http://dx.doi.org/10.1182/blood.v128.22.2294.2294.
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Abstract Introduction Hematopoietic stem cell transplantation from non-sibling donors remains the only curative option for severe aplastic anemia patients refractory to ATG/CsA immunosuppression. Although the results of MUD and haploidentical transplantation in SAA have improved significantly, graft-versus host disease (GVHD) remains a serious problem, associated with significant morbidity and mortality. We investigated the role of new method of graft processing - TCR alpha/beta depletion as a way to improve the results of MUD and haploidentical transplants in SAA. Patients and methods Forty two patients with SAA were treated since November 2012 till February 2016. Median age at HSCT was 11(3-22) years, 27 male/15 female. All pts. were refractory/relapsed (36/6) after at least two courses of ATG/CsA, 3 pts. had concurrent severe hemolytic PNH. Time from diagnosis to transplant was 17(143-8,6)/15(99-5,5) months. Donors were unrelated volunteers in 32 cases, haploidentical parents in 10 cases. Preparative regimen included cyclophosphamide 100-150 mg/kg, fludarabine 150mg/kg, ATG and 2-6Gy thoraco-abdominal irradiation, in haplo transplants patients additionaly received thiophosphamide at 10mg/kg. Two patients recieved alemtuzumab instead of ATG because of anaphylaxis. Post-transplant GVHD prophylaxis included Tacro and Mtx on days +1, +3, +6. PBSC grafts were depleted of TCR alpha/beta cells and CD19 cells with CliniMACS device as recommended by the manufacturer. Patients received a median of 10(6,0-23) x106 CD34 per kg, 8(1-39) x104 TCR alpha/beta per kg. Results All patients engrafted with a median of 15 days for WBC and 13,5 days for platelets. In 4 patients after MUD transplantation secondary graft failure (rejection) developed, two of them were successfully retransplanted. Cumulative incidence of aGVHD 2-3 was 9% (95% CI: 3-27%) and 40%(95% CI: 18-85%) in MUD and haplo respectively, 90% patients with aGVHD had only skin involvement. No grade 4 aGVHD detected. Cumulative incidence of grade 3 aGVHD was 3%(95% CI: 0,5-21%) and 10%(95% CI: 2-64%) in MUD and haplo, respectively. Cumulative incidence of cGVHD was 12%(95% CI: 0,5-58%) and 30%(95% CI: 11-77%) in MUD and haplo respectively. A median follow up is 2 years. Seven patients died of viral infection - CMV (2 pts.), viral infection - CMV plus GVHD (2 pts.), microangiopathy (1 pt), 2 pts. died after second transplantation (1 - disseminated toxoplasmosis, 1 - ADV and CMV and GVHD). Event and GVHD-free survival is 73%(95% CI: 57-89%) and 60% (95% CI: 30-90%) in MUD and haplo respectively (pic.1) Overall survival is 86%(95% CI: 74-99%) and 78%(95% CI: 50-100%) respectively for MUD and haploidentical (pic.2). Prolonged stable mixed chimerism in T-cells was detected in recipients of MUD grafts in contrast to haploidentical grafts (pic/3). Conclusion TCR alpha/beta depletion is a robust platform for allogeneic transplantation from MUD and haploidentical donors in severe aplastic anemia. Results should be further improved by additional measures to control viral infections and prevent rejection in MUD transplants. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
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Schrezenmeier, Hubert, Ulrike Feldmann, Hellmut Ottinger, Matthias Eder, Monika Führer, Hans-Jochem Kolb, Axel Zander, et al. "Allogeneic Stem Cell Transplantation for Acquired Aplastic Anemia: Better Outcome with Bone Marrow as Compared to Peripheral Blood in HLA-Matched Sibling Donor Transplantation and Improved Outcome Over Time After Matched Unrelated Donor Transplantation. A Retrospective Analysis of Transplants Reported to the German Registry for Stem Cell Transplantation (DRST)." Blood 114, no. 22 (November 20, 2009): 876. http://dx.doi.org/10.1182/blood.v114.22.876.876.
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Abstract Abstract 876 Background: Transplantation of bone marrow (BM) from a HLA-matched sibling donor is an effective treatment for severe aplastic anemia (AA) with long-term survival in excess of 80%. In the recent years there were two trends in allogeneic stem cell transplantation (SCT) for AA: (1) increasing proportion of transplants performed from matched unrelated donors (MUD) and (2) increasing proportion of transplants using peripheral blood progenitor cells (PBSC) as stem cell source instead of BM. A similar switch to PBSC over BM grafts is reported in leukemia transplants. PBSC grafts for leukemia are associated with higher rates of chronic graft-versus-host disease (cGVHD). This adverse consequence may be offset by lower rates of leukemia relapse in some settings. In contrast, there is no perceived benefit of cGVHD for AA. A recent retrospective analysis of EBMT/CIBMTR reported worse outcome after PBSCT compared to BMT in young patients after HLA-matched sibling (sib) transplantation. The impact of stem cell source on outcome after MUD transplants has not been studied in detail so far. Some reports on favourable results after MUD SCT prompted the discussion whether MUD SCT should be performed earlier in the treatment algorithm in AA instead of considering it as salvage treatment after failure of immunosuppressive treatment. Therefore we performed a retrospective study on the dataset of the German Registry of Stem Cell Transplantations (DRST) to (1) analyze outcome after MUD compared to sib SCT and (2) to study impact of stem cell source (PBSC vs BM) on both sibling and MUD SCT and (3) to analyze impact of transplant period (1998-2002 vs. 2003-2008). Results: We analyzed 182 sib SCT and 114 MUD SCT (first transplants only). The interval between diagnosis and transplant was significantly longer for MUD SCT as compared to sib SCT (median 98.5 days vs. 511.5 days; p<0.001 ) suggesting that the majority of sib SCT were performed upfront whereas MUD SCT in the majority of cases was performed after failure of other treatments. Median age was 28.5 years (sib SCT) and 30 years (MUD) years (p=0.41). PBSC were used as stem cell source in 50.5% of sib SCT and 61.4% of MUD (p=0.097). 5-year probability of survival was 84.6% (95%-CI: 79.3-90.3%) after sib SCT and 70.1% (95%-CI. 61.8-79.6%) after MUD (p<0.003). In univariate comparison age at transplant has significant impact on survival: After sib SCT 5-year probability of survival in patients ≤ 30 years vs. > 30 years was 94.5% (95%-CI: 90.0-99.3%) vs. 73.5% (95%-CI: 64.3-84.1%)(p<0.001) . 5-year probability of survival after MUD SCT in patients ≤ 30 years vs. > 30 years was 77.7% (95%-CI: 67.3-89.7%) and 60.6 (95%-CI: 48.2-76.2%) (p=0.044). In the most recent period (2003-2008) 2-year probability of survival was 81.6% (95%-CI: 72.9-91.3%) after sib SCT (n=80) and 75.6 (66.1 – 86.5%) after MUD SCT (n=73) (p=0.34). After sib SCT survival was significantly better with BM as compared to PBSCT (5-yr. prob. 95.3%; 95%-CI: 90.9-99.9%; n=89 vs. 74.1%, 95%-CI: 65.1-84.2%; n=92; p<0.001) and cumulative incidence of chronic GvHD was significantly higher with PBSCT as compared to BM (47.0% vs. 18.4%; p<0.01). Cumulative incidence of acute GvHD II-IV did not differ significantly between BM and PBSC. In contrast, stem cells source did neither significantly affect overall survival nor cumulative incidence of acute or chronic GvHD after MUD. In multivariate analysis of the sib SCT older age (>30 years) and use of PBSC were significant risk factors for mortality (Hazard Ratio (HR) 3.4 (1.2-9.3) and HR 4.0 (1.3-12.2). Other variables in the model (conditioning regimen; GvHD prophylaxis; sex match; time diagnosis to transplant and transplant period) were not significant. For MUD SCT none of these variables were significant in a multivariate model. Conclusion: These results indicate that BM grafts should be preferred to PBSC in patients undergoing HLA-identical sib SCT for AA. In contrast, no negative impact of stem cell source on outcome after MUD SCT could be demonstrated. Results of MUD SCT substantially improved over time. In the most recent period from 2003- 2008 the probability of survival after MUD and HLA-identical sib SCT was no longer different. So far majority of MUD transplants were performed late after diagnosis, mostly after failure of immunosuppression. Re-assessment of both the indication of MUD SCT for AA and the timing of MUD SCT is warranted. Supported by the Deutsche José Carreras Leukämie-Stiftung. Disclosures: No relevant conflicts of interest to declare.
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Bociek, R. Gregory, James E. Talmadge, James C. Lynch, Charles A. Enke, Charles A. Kuszynski, Philip J. Bierman, Julie M. Vose, et al. "Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) for Hematologic Malignancies (HM) Using Pentostatin/Low-Dose Total Body Irradiation (TBI)." Blood 106, no. 11 (November 16, 2005): 3671. http://dx.doi.org/10.1182/blood.v106.11.3671.3671.
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Abstract Background/Patients and Methods: NST is increasingly being used as a means of establishing a graft-versus-malignancy (GVM) effect with less regimen related toxicity. Between 9/01 and 7/04, 39 patients (pts) with high risk/relapsed/refractory HM who were not candidates for full intensity allogeneic stem cell transplantation underwent NST using Pentostatin/TBI. The median age of pts was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous stem cell transplantation in 22 pts. Diseases transplanted included chronic lymphocytic leukemia/indolent non-Hodgkin’s lymphoma (NHL, n=6), aggressive NHL (n=8), mantle cell lymphoma (n=3), Hodgkin’s disease (n=6), myeloproliferative disorders (n=4), myelodysplastic syndromes (n=4), and acute myelogenous leukemia (AML, n=8). Conditioning consisted of Pentostatin 4 mg/m2 daily on day −21, −20, and −19, followed by 200 cGy TBI on day −1. Post-grafting immunosuppression consisted of cyclosporine/mycophenolate mofetil. Results: Stem cell transplantation was from matched related (n=14) or unrelated (n=25) donors. Death prior to 100 days post transplant occurred in 7 patients. Grade III/IV toxicities included hematologic (n=10 pts), infectious (n=5) and other non-infectious (n=4). The median nadir values (day −21 to day 0) for hemoglobin, neutrophil count and platelet count were 10.7 g/dl (range 7.8–12), 1056/mm3 (range 0–5336), and 174/mm3 (range 24–523) respectively. Three pts failed to engraft; two patients with myelofibrosis (both of whom had autologous reconstitution) and one patient with high risk AML (who died of complications of fungal sepsis without hematologic recovery). The median chimerism values for CD3+ cells and WBC at day 28 are 80% and 95% donor cells respectively. The median chimerism values for CD3+ and WBC at day 70 are 95% and 95% respectively. There have been no late graft failures. The cumulative incidence of all grades of acute graft-versus-host disease at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%, P=0.012). Chronic graft-versus-host disease has developed in 69% of patients. The cumulative incidence of relapse for all patients is 30%, and is lower for unrelated donor transplants than matched related donor transplants (46% vs. 20%, P=0.02). The probability of event-free and overall survival at two years is 52% and 56% respectively. Conclusions: This regimen is associated with acceptable toxicity. Engraftment has not been an issue with the exception of two pts with myelofibrosis. Pts receiving unrelated donor grafts have a higher incidence of graft-versus-host disease and a lower relapse rate. This represents indirect support for the presence of a GVM effect. A prospective study using a modified Pentostatin schedule (starting at day − 10) is ongoing based on the nadir of host T-cells identified in this study.
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Gajewski, JL, LD Petz, L. Calhoun, S. O'Rourke, EM Landaw, NR Lyddane, LA Hunt, GJ Schiller, WG Ho, and RE Champlin. "Hemolysis of transfused group O red blood cells in minor ABO- incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate." Blood 79, no. 11 (June 1, 1992): 3076–85. http://dx.doi.org/10.1182/blood.v79.11.3076.3076.
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Abstract Hemolysis most commonly occurs following bone marrow transplant when there is “minor” ABO blood group incompatibility between donor and recipient. The hemolysis has been attributed to destruction of the patient's incompatible erythrocytes by donor-derived anti-A and/or anti- B antibody produced from “passenger” immunocompetent donor lymphocytes. Extraordinary transfusion requirements of group O erythrocytes in a series of patients receiving unrelated minor ABO-incompatible marrow grafts led us to investigate whether this mechanism could account for the extent of hemolysis observed. In seven consecutive minor ABO- incompatible unrelated-donor bone marrow transplant recipients receiving cyclosporine without posttransplant methotrexate, we observed excessive hemolysis. For cases in this index group, a strongly reactive donor-derived ABO blood group antibody was identified coincident with development of hemolysis. Transfusion requirements in the first three patients (26 U of group O erythrocytes each) greatly exceeded the recipient's volume of incompatible erythrocytes, indicating that lysis of transfused group O erythrocytes was also occurring. Pretransplant erythrocyte exchange transfusion with group O erythrocytes performed in the four subsequent patients decreased the severity of hemolysis, but did not prevent it. Among minor ABO-incompatible marrow graft recipients, an analysis of variance demonstrated effects on transfusion requirements due to donor-recipient relationship being unrelated (P less than .002) and the use of posttransplant methotrexate (P = .0001), and there was interaction between these two factors (P less than .001). Bone marrow transplants from unrelated donors resulted in an exaggerated immune response to ABO blood group antigens, which was associated with hemolysis of transfused group O erythrocytes, as well as the patient's ABO-incompatible erythrocytes. This serious complication may be prevented by posttransplant immunosuppression with methotrexate.
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Gajewski, JL, LD Petz, L. Calhoun, S. O'Rourke, EM Landaw, NR Lyddane, LA Hunt, GJ Schiller, WG Ho, and RE Champlin. "Hemolysis of transfused group O red blood cells in minor ABO- incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate." Blood 79, no. 11 (June 1, 1992): 3076–85. http://dx.doi.org/10.1182/blood.v79.11.3076.bloodjournal79113076.
Full textAbstract:
Hemolysis most commonly occurs following bone marrow transplant when there is “minor” ABO blood group incompatibility between donor and recipient. The hemolysis has been attributed to destruction of the patient's incompatible erythrocytes by donor-derived anti-A and/or anti- B antibody produced from “passenger” immunocompetent donor lymphocytes. Extraordinary transfusion requirements of group O erythrocytes in a series of patients receiving unrelated minor ABO-incompatible marrow grafts led us to investigate whether this mechanism could account for the extent of hemolysis observed. In seven consecutive minor ABO- incompatible unrelated-donor bone marrow transplant recipients receiving cyclosporine without posttransplant methotrexate, we observed excessive hemolysis. For cases in this index group, a strongly reactive donor-derived ABO blood group antibody was identified coincident with development of hemolysis. Transfusion requirements in the first three patients (26 U of group O erythrocytes each) greatly exceeded the recipient's volume of incompatible erythrocytes, indicating that lysis of transfused group O erythrocytes was also occurring. Pretransplant erythrocyte exchange transfusion with group O erythrocytes performed in the four subsequent patients decreased the severity of hemolysis, but did not prevent it. Among minor ABO-incompatible marrow graft recipients, an analysis of variance demonstrated effects on transfusion requirements due to donor-recipient relationship being unrelated (P less than .002) and the use of posttransplant methotrexate (P = .0001), and there was interaction between these two factors (P less than .001). Bone marrow transplants from unrelated donors resulted in an exaggerated immune response to ABO blood group antigens, which was associated with hemolysis of transfused group O erythrocytes, as well as the patient's ABO-incompatible erythrocytes. This serious complication may be prevented by posttransplant immunosuppression with methotrexate.
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Lin, H., S. F. Bolling, P. S. Linsley, R. Q. Wei, D. Gordon, C. B. Thompson, and L. A. Turka. "Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion." Journal of Experimental Medicine 178, no. 5 (November 1, 1993): 1801–6. http://dx.doi.org/10.1084/jem.178.5.1801.
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Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.
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Jhaveri, Amy, Esperanza B. Papadopoulos, Ann A. Jakubowski, Farid Boulad, Nancy A. Kernan, Trudy N. Small, Miguel-Angel Perales, et al. "Improved Survival in Patients with Refractory Cytopenias (Low Risk Myelodysplastic Syndrome - MDS) Treated with Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplants (allo TCD-HSCTs),." Blood 118, no. 21 (November 18, 2011): 3831. http://dx.doi.org/10.1182/blood.v118.21.3831.3831.
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Abstract Abstract 3831 Background: Controversy exists regarding optimal treatment for pts with MDS with low blast percentages. Benefits of early transplant versus transplant-related morbidity and mortality have been debated. With increased time to transplant, MDS pts are more likely to undergo increased numbers of blood transfusions, experience more cytopenias, and are at risk of disease progression. Transplant offers a cure for MDS, and advances in supportive care during and after transplantation have afforded better outcomes and increased numbers of older pts to undergo transplant. Depletion of mature T cells from allogeneic HSCTs decreases the incidence of GvHD and its associated morbidity and mortality. This study therefore evaluated outcomes of pts with refractory cytopenias with less than 5% marrow blasts, who underwent T-cell depleted HSCTs from matched or mismatched, related or unrelated donors at a single center. Patients and Methods: Between February 1982 and May 2010, 44 pts with refractory cytopenias(marrow blasts <5%) underwent alloTCD-HSCTs at MSKCC. Thirty pts had de novo MDS, 8 therapy-related, and 6 post aplastic anemia. Median age was 37 yrs (range 9.5–63.5). The MDS subtypes by WHO criteria were: refractory anemia (10), refractory anemia/cytopenia with ringed sideroblasts (2), and refractory cytopenia with multilineage dysplasia (32). Prognosis and risk categories at diagnosis in pts with de novo and post aplastic anemia were determined using 3 scoring systems. Prognosis by IPSS was: low risk (2), intermediate risk-1 (32), intermediate risk-2 (2), unknown (2 – no cytogenetic studies); by WPSS criteria: very low (1), low (12), intermediate (16), high (7), unknown (2); and by MDACC criteria in 34 pts: category-1 (lower risk) (6), category-2 (27), category 3-(1). All pts were severely cytopenic and/or transfusion or cytokine-dependent before alloTCD-HSCT. The median time from diagnosis to transplant was 0.6 years (range 0.11–7.87). Pts were conditioned for transplant with regimens that either included high dose TBI plus chemotherapy (26) or chemotherapy only but including IV busulfan (18). Anti-thymocyte globulin was given for rejection prophylaxis to 40 pts. HSCT donors were: siblings (24) or unrelated donors (20); 12 of the 44 donors were mismatched. Stem cell source was bone marrow (22) or GCSF-primed peripheral blood (22). T cells were removed ex-vivo from the bone marrow grafts with soybean lectin agglutinin and rosetting with sheep red blood cell (sRBC) and from the peripheral blood stem cell grafts by positive selection with a CD34 antibody (Isolex) followed by sRBC rosetting. No posttransplant immunosuppression was given. Results: Forty-one of the 43 pts evaluable for engraftment recovered ANC >500cells/uL at a median of 11d (range: 9–22). Two pts had primary graft failure, and 3 had secondary graft failure. Four of these pts underwent second transplants. Acute GvHD, grade 1–2, developed in 3 pts. Three additional pts developed grade 3 GvHD, 2 after DLI given for refractory opportunistic infections and 1 after a second unmodified transplant for graft failure. Chronic GvHD occurred in 3 pts, one of whom had received a second unmodified transplant for graft failure. As of May 2011, 16 pts have expired. Causes of death included: GvHD (5, including post DLI), infections (5), graft failure/poor graft function (3), regiment-related toxicity (2), and late death due to lung cancer (1). Twenty-eight pts are alive and doing well with a median survival of 2.8 years (range: 0.5–21.43). The 2-year and 5-year survivals are: 70.1% and 63.3%. Younger recipient age (<50), favorable MDACC score, chemotherapy only preparative regimen, and recent transplants (≥ 2000) indicated a better survival but differences did not reach statistical significance. Survival was not associated with etiology, HLA matching, source of stem cells, IPSS, or WPSS in this series of patients. Conclusion: Treatment of MDS pts with refractory cytopenias with alloTCD-HSCTs from matched and mismatched related and unrelated donors cures >60% of pts beyond 5 years, with a low incidence of acute and chronic GvHD. These findings support early transplant in the treatment of MDS with refractory cytopenias, especially in younger pts. Disclosures: Small: Pfizer, Inc: Equity Ownership, family member employed by Pfizer, Inc.
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Bethge, Wolfgang A., Ute Hegenbart, Monic J. Stuart, Barry E. Storer, Michael B. Maris, Mary E. D. Flowers, David G. Maloney, et al. "Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning." Blood 103, no. 3 (February 1, 2004): 790–95. http://dx.doi.org/10.1182/blood-2003-07-2344.
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AbstractThis study retrospectively analyzed data from 446 patients given hematopoietic cell transplants from HLA-matched related or unrelated donors after conditioning with 2 Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine following grafting. Fifty-three of 446 patients received donor lymphocyte infusion (DLI) with a median CD3 dose of 1 × 107 cells/kg. Their diagnoses included myelodysplastic syndrome (n = 10), acute leukemia (n = 10), chronic leukemia (n = 11), multiple myeloma (n = 9), lymphoma (n = 9), and solid tumors (n = 4). Patients received DLI for persistent disease (n = 8), disease relapse (n = 17), progressive disease (n = 12), low donor chimerism with disease (n = 11), or low chimerism with disease remission (n = 5). Seventeen of the 53 patients (32%) are alive with a median follow-up of 30 months; 5 are in complete remission (CR), 2 are in partial remission (PR), and 10 have stable or progressive disease. Nine of 53 patients (17%) developed grades II to IV acute graft-versus-host disease. Of 48 patients receiving DLI for treatment of disease, 7 achieved CR and 5 PR, with an overall response rate of 25%. Six of 16 patients who received DLI for chimerism had increases in donor chimerism leading to sustained engraftment, whereas 10 eventually rejected their grafts. In conclusion, DLI is a potential treatment strategy, with acceptable toxicity, for patients with persistent, relapsed, or progressive disease after nonmyeloablative hematopoietic cell transplantation.
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Karch, Jon, Eric Schaefer, W. Chritopher Ehmann, Michelle Carraher, Giampaolo Talamo, Witold B. Rybka, and David F. Claxton. "Long Term Survival After Sirolimus Based Non-Ablative Alternative Donor Transplantation." Blood 114, no. 22 (November 20, 2009): 1212. http://dx.doi.org/10.1182/blood.v114.22.1212.1212.
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Abstract Abstract 1212 Poster Board I-234 Background: The use of sirolimus (rapamycin) as primary immunosuppression for allogeneic blood and marrow transplantation is logical given its favorable anti-tumor and tolerance inducing properties. Methods: After IRB approval, we analysed long term survival and predictive correlates in 92 patients receiving sirolimus based non-ablative alternative donor hematopoietic transplantation for hematological malignancies. All received conditioning with a purine nucleotide and cyclophosphamide 1mg/m2 (d-7, -6), 5mg/m2 methotrexate days 1, 3, 6 and combination sirolimus and tacrolimus each dosed at 6-10 ng/ml levels. Where feasible tacrolimus was discontinued as early as day 50, but sirolimus was continued until at least 9 months unless discontinued for toxicity or relapse. Median age was 57 years (range 23-74). Diagnoses were ALL – 4, AML – 44, CLL – 7, CML – 4, HD – 3, MDS – 4, MM – 2, MPD – 4, NHL – 19, AA-1. Only 32/92 patients were in complete remission (CR) at the time of transplant and only 16 in CR1. Median number of prior chemotherapy regimens was 3 (0-7). CIBMTR risk scores for outcome were: high in 43, intermediate in 28, and low in 20. 11 patients had received prior autologous transplantation (12%). Donors were unrelated (URD) in 80 (87%) patients and 5/6 antigen matched related in 12 (13%). 57 of 80 URD recipients were transplanted with cells matched at HLA A,B,C and DRB1, while the other 23 received cells mismatched at least 1 locus. 86/92 patients received transplants of G-CSF mobilized blood cells, the other 6/92 received bone marrow (all URD). Hospital discharge was generally day 1 post transplant and many engrafted as out patients. Results: Patients were hospitalized a median of only 9 of the initial 100 days post transplant (range 1-66 days). Median follow-up of the 39 surviving patients was 1025 days (214-2414) from transplantation. Primary graft failure (< 10% donor engraftment in survivors at day 30) occurred in 8/92 patients, and secondary graft failure developed in 3/92. In 44/92 (47.8%) tacrolimus was discontinued prior to day 100. Graft versus host disease (GVHD) developed by day 100 in 45/85 patients followed at least 100 days. Median overall survival (OS) was 480 days. OS for AML (44 patients) and NHL(19) +CLL(7) patients is shown in the figure below. Of pre-transplant features, only stage (CR vs other) predicted for OS (p=0.01). Donor chimerism at 100 days was also predictive for OS (HR=0.33, p=0.02). Increased chimerism was correlated with HLA matched grafts (p=0.02) and with increased numbers of infused donor CD34+ve cells (p=0.04). Treatment related mortality was 9/92 (9.8%) at 100 days and 18/85 (21%) at 1 year. Conclusions: Sirolimus treatment with early discontinuation of tacrolimus provides effective GVHD prophylaxis and acceptable long-term survival in a group of older, poor prognosis patients receiving non-ablative allogeneic transplants from alternative donors for hematological malignancies. Measures to further improve day 100 donor chimerism, including improved HLA matching and higher infused numbers of CD34 +ve cells, may yield further improvements. Disclosures: No relevant conflicts of interest to declare.
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Pavletic, Steven Z., Shelly L. Carter, Nancy A. Kernan, Jean Henslee-Downey, Adam M. Mendizabal, Esperanza Papadopoulos, Roger Gingrich, James Casper, Saul Yanovich, and Daniel Weisdorf. "Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation." Blood 106, no. 9 (November 1, 2005): 3308–13. http://dx.doi.org/10.1182/blood-2005-04-1614.
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AbstractDonor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.
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Hale, Geoff, Mei-Jie Zhang, Donald Bunjes, H. Grant Prentice, David Spence, Mary M. Horowitz, A. John Barrett, and Herman Waldmann. "Improving the Outcome of Bone Marrow Transplantation by Using CD52 Monoclonal Antibodies to Prevent Graft-Versus-Host Disease and Graft Rejection." Blood 92, no. 12 (December 15, 1998): 4581–90. http://dx.doi.org/10.1182/blood.v92.12.4581.424k22_4581_4590.
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Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T-cell depletion increases the risk of graft rejection. This study examined the use of CD52 monoclonal antibodies to eliminate T cells from both donor marrow and recipient to prevent both GVHD and rejection. Seventy patients receiving HLA-identical sibling transplants for acute myelogenous leukemia (AML) in first remission were studied. An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft infusion. No posttransplant immunosuppression was given. Results were compared with two control groups: (1) 50 patients who received bone marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received nondepleted grafts and conventional GVHD prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The incidence of acute GVHD was 4% in the treatment group compared with 35% in the CyA/MTX group (P < .001). Chronic GVHD was also exceptionally low in the treatment group (3% v 36%; P< .001). The problem of graft rejection, which had been frequent in the historic CAMPATH-1M group (31%), was largely overcome in the treatment group (6%). Thus, transplant-related mortality of the treatment group (15% at 5 years) was lower than for the CyA/MTX group (26%; P = .04). There was little difference in the risk of leukemia relapse between the treatment group (30% at 5 years) and the CyA/MTX group (29%). Survival of the treatment group at 6 months was better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and neither was the difference in leukemia-free survival (60% v52%). We conclude that T-cell depletion is a useful strategy to prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and practical method to do this. At least in AML, the beneficial reduction in GVHD can be achieved without an increased risk of relapse.
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Shurey, S. "UK based microsurgical training." Issues of Reconstructive and Plastic Surgery 24, no. 1 (May 20, 2021): 48–55. http://dx.doi.org/10.52581/1814-1471/76/5.
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This describes the UK history of the evolution of microsurgical training. The author has been involved since the start in 1979 and took a sole teaching role in the courses 2 years later. Before teaching microsurgery the necessary skills were obtained by the performance of various organ transplants in mice, rats and rabbits to investigate organ storage and immunosuppression. This experience identified the pitfalls of microsurgery and amplified the then identified need for meticulous microsurgical training. A basic microsurgical program was then instigated to provide step by step exercises of increasing difficulty. This consisted of microscope set-up, correct positioning, instruments, simulated suture exercises, dissection techniques, end to end arterial and venous anastomosis, end to side anastomosis, interpositional vein grafts, nerve anastomosis and groin flaps – all performed on an anaesthetised rat. Latterly we are now running advanced workshops incorporating supramicrosurgical exercises in the chicken (thigh) and the rat. The microsurgical workshops are still running 41 years later!
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Mielcarek, Marco, Barry Storer, Christoph Kahl, Brenda M. Sandmaier, David Maloney, Mike B. Maris, and Rainer Storb. "Nonmyeloablative and Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies: Outcomes with HLA-Matched Unrelated Donors Compared to HLA-Identical Sibling Donors." Blood 106, no. 11 (November 16, 2005): 658. http://dx.doi.org/10.1182/blood.v106.11.658.658.
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Abstract For most hematologic malignancies treated by myeloablative conditioning, hematopoietic cell transplantation (HCT) from HLA-matched unrelated donors has been associated with greater non-relapse mortality (NRM) and worse overall survival (OS) than that from HLA-identical sibling donors. Poorer outcomes with unrelated grafts are largely related to more frequent or severe graft-versus-host disease (GVHD), and higher rates of graft failure. In this retrospective analysis we asked whether outcomes of patients with hematologic malignancies who had nonmyeloablative HCT also differed according to donor type. The analysis included all donor/recipient pairs for whom HLA-A, -B, -C, -DR, and DQ allele-level typing information was available. Single allele-level mismatches at HLA class I were allowed. Using these criteria, 308 patients given nonmyeloablative HCT (sibling donors, n=187; unrelated donors, n=121) and 849 patients with myeloablative HCT (sibling donors, n=576; unrelated donors, n=273) between 1997 and 2003 were included. The median ages (range) of nonmyeloablative and myeloablative HCT recipients were 54 (9–72) years and 41 (1–65) years, respectively. The nonmyeloablative regimen consisted of 2 Gy total body irradiation (TBI) with or without fludarabine followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine (CSP). Recipients of myeloablative transplants were prepared with different high-dose (TBI-based, 45%; non-TBI-based, 55%) regimens, and the majority (78%) was given methotrexate and CSP for GVHD prophylaxis. G-CSF-mobilized blood was the source of stem cells for all nonmyeloablative transplant recipients, and for 43% of recipients of myeloablative transplants; 57% received bone marrow. Analyses of outcomes used proportional hazard models stratified on diagnosis/disease status, and adjusted for patient age and stem cell source (Table). Our results confirmed that myeloablative HCT from HLA-matched unrelated donors was associated with increased NRM compared to HCT from HLA-identical sibling donors, translating into significantly decreased overall survival for low-risk patients (acute leukemias in first remission, chronic myeloid leukemia in chronic phase, low-risk myelodysplasia). In contrast, a detrimental impact on outcome with unrelated grafts was not appreciable after nonmyeloablative conditioning. Within the limitations of a retrospective analysis, these data suggest that donor type does not influence outcome following nonmyeloablative HCT. Thus, depending on the likely duration and success of a donor search, and the availability of other treatment options, unrelated donor transplantation may be an option for patients who are candidates for nonmyeloablative HCT but who do not have a suitable sibling donor. OS and NRM with HLA-identical sibling (MSD) vs HLA-matched unrelated (MUD) donors according to type of conditioning Nonmyeloablative Myeloablative N (MSD/MUD) HR (95% CI) P N (MSD/MUD) HR (95% CI) P HR, hazard ratio; CI, confidence interval. HR <1 indicates more favorable, and >1 less favorable outcomes for MUD grafts. Low-Risk OS 21/17 0.23 (0.0–1.9) 0.17 288/152 1.89 (1.3–2.8) 0.001 NRM 0.33 (0.0–2.7) 0.30 2.12 (1.4–3.3) 0.001 High-Risk OS 166/104 1.08 (0.7–1.6) 0.71 288/121 1.09 (0.8–1.5) 0.59 NRM 0.93 (0.5–1.6) 0.80 1.54 (1.0–2.3) 0.05
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Symons, Heather J., Xiaobu Ye, Leo Luznik, Michele Phelps, Angelita Crawford, M. Yair Levy, Richard J. Jones, and Ephraim J. Fuchs. "Low Incidence of CMV Reactivation and Infectious Morbidity and Mortality after Nonmyeloablative Haploidentical Bone Marrow Transplantation Incorporating Post-Transplantation Cyclophosphamide." Blood 106, no. 11 (November 16, 2005): 3245. http://dx.doi.org/10.1182/blood.v106.11.3245.3245.
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Abstract Graft rejection, severe graft-versus-host disease (GVHD), and prolonged immunosuppression are major complications of partially HLA-mismatched, or haploidentical, stem cell transplantation in humans. Intensive conditioning of the recipient and rigorous T cell depletion of the donor graft reduces the risk of the first two complications, but may prolong or intensify post-transplantation immunodeficiency, increasing the patient’s susceptibility to opportunistic infection. In contrast, alloreactive T cells may be selectively eliminated in vivo by the early post-transplantation administration of high dose cyclophosphamide (Cy), leaving virus or other pathogen specific resting memory T cells relatively unharmed. To test this hypothesis, we have analyzed the infectious complications in 60 patients who were enrolled in a clinical trial of nonmyeloablative haploidentical bone marrow transplantation (“mini-haploBMT”) incorporating post-transplantation Cy. All patients received fludarabine 30mg/m2/dose on days -6 to -2, Cy on day -2, and 200 cGy total body irradiation (TBI) on day -1. The first 20 patients received a single dose of 50 mg/kg Cy IV on day 3, whereas the final 40 patients received the same dose of Cy on day 3 and 4. The median age of transplant recipients was 48years (1-71years), 12 patients had 13 prior autologous transplants prior to enrollment, and patients had an average of 2.7 treatment regimens prior to transplant (0–8). Patients received a median of 1.27x 108/kg mononuclear cells/kg with 3.9 x 106 CD34+ cells/kg. The median follow-up at the time of this analysis was 245.5 days (41–1550 days). An ANC >500/mm3 was achieved a median of day 16 (12–208). Only 5 patients (8.3%) died from infectious related causes. Of these, 3 were known to have relapsed disease. There were 34 patient/donor pairs (56.6%) at risk for CMV reactivation. In these pairs, only 6 patients developed CMV reactivation (17.6%), and 2 patients developed CMV infection. 3 patients with CMV reactivation received one dose of post-transplant Cy, and 3 patients received two. Both patients who developed CMV infections received only dose of post transplant Cy. 23% (14/60) of patients developed an invasive fungal infection, of which 21.4% (3/14) developed in the first 30 days post transplant, 14.3% (2/14) developed between days 31–60, 14.3% (2/60) developed between days 61–100, and 50% (7/14) occurred more then 100 days post transplant. 15% (9/60) had at least one systemic viral infection (other then CMV), of which 22.2% (2/9) developed in the first 30 days post-transplant and 77.8% (7/9) developed more then 90 days post transplant. No patients developed viral infections between days 31–100. These rates of infection compare favorably to the rates of infection seen in patients receiving haploidentical grafts following myeloablative conditioning without post-transplantation Cy. We propose that the very low numbers of patients with CMV reactivation, fungal or viral infections, and infectious related mortality is secondary to early engraftment, low rates of Grade 3–4 GVHD (7/60 patients, 11.7%; 5/7 patients received one dose of post-transplant Cy, 2 received two) or prolonged immunosuppression, and an intact host B cell and memory T cell function preserved with this novel prep regimen and T cell replete graft.
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Storb, Rainer, Cong Yu, Todd Barnett, John L. Wagner, H. Joachim Deeg, Richard A. Nash, Hans-Peter Kiem, et al. "Stable Mixed Hematopoietic Chimerism in Dog Leukocyte Antigen–Identical Littermate Dogs Given Lymph Node Irradiation Before and Pharmacologic Immunosuppression After Marrow Transplantation." Blood 94, no. 3 (August 1, 1999): 1131–36. http://dx.doi.org/10.1182/blood.v94.3.1131.415k21_1131_1136.
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Stable mixed donor/host hematopoietic chimerism can be accomplished in dog leukocyte antigen (DLA)-identical littermate dogs given sublethal (200 cGy) total-body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were based on the hypothesis that drugs that prevent graft-versus-host disease (GVHD) after transplant also suppress host-versus-graft (HVG) reactions and thereby enhance engraftment. Here, we asked whether pretransplant TBI provided marrow space for the graft to home or caused host immunosuppression. To address the questions, recipients were given pretransplant irradiation to cervical, thoracic, and abdominal lymph nodes (except pelvis), DLA-identical littermate marrow grafts, and MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1 died with GVHD and engraftment, and 3 are alive as mixed chimeras after 57 to 97 weeks. Four dogs given 200 cGy irradiation also showed initial engraftment, but rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in nonirradiated marrow and lymph node spaces and involved granulocytes, T cells, and monocytes. While other explanations are possible, results seem consistent with the hypothesis that pretransplant radiation provides host immunosuppression, and grafts can create their own marrow space. These data set the stage for the development of novel transplant regimens that substitute immunosuppressive for cytotoxic agents.
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Hale, Geoff, Mei-Jie Zhang, Donald Bunjes, H. Grant Prentice, David Spence, Mary M. Horowitz, A. John Barrett, and Herman Waldmann. "Improving the Outcome of Bone Marrow Transplantation by Using CD52 Monoclonal Antibodies to Prevent Graft-Versus-Host Disease and Graft Rejection." Blood 92, no. 12 (December 15, 1998): 4581–90. http://dx.doi.org/10.1182/blood.v92.12.4581.
Full textAbstract:
Abstract Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T-cell depletion increases the risk of graft rejection. This study examined the use of CD52 monoclonal antibodies to eliminate T cells from both donor marrow and recipient to prevent both GVHD and rejection. Seventy patients receiving HLA-identical sibling transplants for acute myelogenous leukemia (AML) in first remission were studied. An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft infusion. No posttransplant immunosuppression was given. Results were compared with two control groups: (1) 50 patients who received bone marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received nondepleted grafts and conventional GVHD prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The incidence of acute GVHD was 4% in the treatment group compared with 35% in the CyA/MTX group (P < .001). Chronic GVHD was also exceptionally low in the treatment group (3% v 36%; P< .001). The problem of graft rejection, which had been frequent in the historic CAMPATH-1M group (31%), was largely overcome in the treatment group (6%). Thus, transplant-related mortality of the treatment group (15% at 5 years) was lower than for the CyA/MTX group (26%; P = .04). There was little difference in the risk of leukemia relapse between the treatment group (30% at 5 years) and the CyA/MTX group (29%). Survival of the treatment group at 6 months was better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and neither was the difference in leukemia-free survival (60% v52%). We conclude that T-cell depletion is a useful strategy to prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and practical method to do this. At least in AML, the beneficial reduction in GVHD can be achieved without an increased risk of relapse.
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Daneshgaran, Giulia, Carrie S. Stern, and Evan S. Garfein. "Reporting Practices on Immunosuppression and Rejection Management in Face Transplantation: A Systematic Review." Journal of Reconstructive Microsurgery 35, no. 09 (June 6, 2019): 652–61. http://dx.doi.org/10.1055/s-0039-1691787.
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Background Face transplantation is a demanding operation requiring complex planning and expert technical performance. While the documentation of successes of the first transplants is impressive, there are lacunae in reporting of institutional protocols for other critical operation components, namely, immunosuppression, graft surveillance, and management of rejection and graft failure. The purpose of this review is to assess protocol reporting by face transplant teams to determine where we, as a plastic surgery community, can improve. Methods A systematic review of PubMed was conducted to identify literature on face transplants published from November, 2005, starting with the first successful transplant to December, 2018. English-language articles were reviewed for reporting of protocols on antimicrobial prophylaxis, immunosuppression, graft surveillance, and management of rejection and graft failure. Results A total of 44 face transplantation patients were identified. Protocols for antimicrobial prophylaxis, immunosuppressive induction, and maintenance immunosuppression were reported for 61%, 75%, and 73% of patients, respectively. Protocols for graft surveillance and medical management of rejection were reported for 70% of patients in both cases. Surgical salvage strategies to manage graft failure were documented for 43% of patients. Conclusion The current literature on face transplantation does not include consistent reporting on critical aspects of patient care. Medical protocols outlining guidelines for immunosuppression, graft surveillance, and management of rejection and graft failure are the most critical factors determining overall transplant success. However, they are underreported in the literature. Development and communication of standardized protocols is essential to improve patient outcomes and maximize the results of this procedure.
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Meyer, Everett H., Rasmus Hoeg, Anna Moroz, Bryan Xei, Hsin-Hsu Wu, Rahul Pawar, Kartoosh Heydari, et al. "Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute Gvhd with Less Immunosuppression in an Early Multicenter Experience with Myeloablative HLA-Matched Transplants." Blood 136, Supplement 1 (November 5, 2020): 47–48. http://dx.doi.org/10.1182/blood-2020-142974.
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BACKGROUND GVHD remains a frequent and serious complication of HSCT despite the decades-long use of standard immunosuppression, such as tacrolimus and methotrexate, as prophylaxis against GVHD. Preclinical models have shown that the timed infusion of donor-derived high-purity CD4+CD25+FOXP3+ regulatory T cells (Treg) preceding adoptive transfer of conventional T cells (Tcon) prevents GVHD and maintains anti-cancer immunity without the need of pharmacologic agents. Early clinical trials using purified Treg-engineered graft showed safety and feasibility, but more extensive clinical studies are needed to test scalability and efficacy. Orca-T is an industry-manufactured, precision-engineered CD34-selected, Treg-engineered graft made in a central GMP laboratory and distributed to multiple centers in the U.S. We present our early patient experience with Orca-T in an ongoing single center phase 2 trial and a multicenter Phase Ib trial and report a pre-planned evaluation of patients randomized to receive Orca-T plus single-agent GVHD prophylaxis (PPX) or Orca-T and no PPX. METHODS 51 patients with high risk or active hematologic malignancies undergoing myeloablative conditioning were enrolled on two trials: a single-center Phase I/II (n=40, NCT01660607) and a multicenter Phase Ib (n=11; NCT04013685) study. Patients received CD34-selected cells infused with highly purified Treg (target dose: 3.0 x 106 cells/kg) followed 2 days later by the infusion of Tcon (3.0 x 106 cells/kg). Initial GMP manufacturing was demonstrated at Stanford (n=9 grafts; 2016 - 2019) and then transferred to Orca Bio in 2019 for scaled production. We evaluated the 34 patients beyond dose escalation since July 2016 who received Orca-T grafts from either matched related (n=25) or unrelated (n=9) donors and single agent GVHD PPX with either tacrolimus (n=28) or sirolimus (n=6). For comparative analysis, we identified a contemporaneous SOC cohort at Stanford (n=138) with both matched related (n=79) and unrelated (n=59) transplant recipients who received unmanipulated PBSC products (median f/u 546 days) and methotrexate plus tacrolimus. In April 2019, enrollment on a phase 2, stage 1 pre-planned subgroup of 24 patients were randomized to test whether all GVHD PPX could be removed: Orca-T plus either single-agent PPX (Arm 1, n=12) or no PPX (Arm2, n=12). RESULTS The Orca-T drug products were manufactured reliably with high Treg purity (93.8% +/- 3.1%) and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between arms and trials). Central lab turn-around times were 25.3 +/- 3.0 hours and all vein-to-vein times were less than 72 hrs (Table 1). For trial participants, there were no manufacturing failures, engraftment failures or treatment related mortality. Orca-T patients vs. SOC showed earlier neutrophil (median of 11 days vs. 14 days, p<0.0001 by Mann-Whitney U) and platelet engraftment (11 vs 17 days, p<0.0001) and a shorter hospital stay (15 vs 19 days, p=0.0002). Patients across 4 clinical sites received Orca-T plus single agent GVHD PPX (n=34; median f/u 261 days) had an acute GVHD grade 2-4 incidence of 0% as compared to 33% in the SoC cohort (n=138, p=0.0018 by Log-rank Mantel-Cox test, Fig. 1). The rate of moderate to severe chronic GVHD for Orca-T patients was 4% vs. 44% in the SoC cohort (p=0.016). In a preliminary subset of evaluable Orca- T patients, GVHD & relapse free survival (GRFS) at one year was higher for Orca-T patients vs SoC (69% versus 33%, p=0.006) while relapse and overall survival did not appear to differ. We observed no differences in infectious complications. In patients randomized to PPX vs. no PPX, the incidence of aGVHD grade 2-4 was 0% in Arm 1 and 58% in Arm 2 (p <0.0001, Log-rank Mantel-Cox test), with 17% of these events being Grade 3-4. All GVHD in Arm 2 responded to steroids with no GVHD-related deaths. CONCLUSIONS Manufacture of high precision Orca-T Treg-engineered donor products were successfully scaled in a central GMP with reliable distribution to centers. Patients who received Orca-T and single agent PPX had no grade 2 or greater acute GVHD acute and very little chronic GVHD when compared to SOC. Patients randomized to Orca-T and no PPX showed an increased incidence of acute GVHD vs. those with Orca-T and single agent PPX. Engineered Treg grafts show promise to improve GFRS and other transplant outcomes. Orca-T has been granted RMAT status by the FDA and evaluation continues in an ongoing multicenter clinical trial. Disclosures Meyer: Orca Bio: Research Funding. Moroz:Orca Bio: Research Funding. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Muffly:Servier: Research Funding; Adaptive: Research Funding; Amgen: Consultancy. Rezvani:Pharmacyclics: Research Funding. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Fernhoff:Orca Bio: Current Employment, Current equity holder in private company. Putnam:Orca Bio: Current Employment, Current equity holder in private company. McClellan:Orca Bio: Current Employment, Current equity holder in private company. Shaw:Orca Bio: Consultancy. McGuirk:Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pluristem Ltd: Research Funding. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Negrin:Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; UpToDate: Honoraria; Amgen: Consultancy; BioEclipse Therapeutics: Current equity holder in private company.
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Hess, Brian T., Feng Gao, John F. DiPersio, Peter Westervelt, Ravi Vij, Geoffrey L. Uy, Keith Stockerl-Goldstein, et al. "Use of Post-Transplant Cyclophosphamide (PTCy) with Mycophenolate Mofetil and Tacrolimus in HLA Matched Allogeneic Hematopoietic Cell Transplant Is Safe and Associated with Acceptable Transplant Outcomes." Blood 126, no. 23 (December 3, 2015): 1950. http://dx.doi.org/10.1182/blood.v126.23.1950.1950.
Full textAbstract:
Abstract Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution. Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method. Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%. Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. Disclosures Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.
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Yakubu, Idris, Abdolreza Haririan, Stephen Bartlett, and Tracy Sparkes. "Successful Renal Transplantation between Identical Twins with Very Brief Immunosuppression." Case Reports in Transplantation 2018 (June 27, 2018): 1–5. http://dx.doi.org/10.1155/2018/9842893.
Full textAbstract:
Renal transplantation between monozygous identical twins provides an opportunity to utilize minimal immunosuppression to maintain stable allograft function, thereby alleviating the toxicities of immunosuppressive therapy. Despite monozygosity, there is a possibility of discordant protein presentation in identical twins that could trigger alloimmune response and lead to graft injury. Therefore, the optimal immunosuppression regimen in this patient population is unknown, and the safety of immunosuppression withdrawal remains controversial. Herein, we describe two patients who underwent successful renal transplantation from monozygotic identical twin donors. Monozygosity was determined using short tandem repeat (STR) analysis. All immunosuppression was successfully discontinued at 2 days and 3 weeks, respectively, after transplantation. Both patients are alive with functioning renal grafts at 1 year and 5 years after transplant, respectively. These two cases suggest that immunosuppression can be withdrawn safely and rapidly in select monozygous identical twin renal transplant recipients.
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von Bueltzingsloewen, A., R. Belanger, C. Perreault, Y. Bonny, DC Roy, Y. Lalonde, J. Boileau, J. Kassis, R. Lavallee, and M. Lacombe. "Acute graft-versus-host disease prophylaxis with methotrexate and cyclosporine after busulfan and cyclophosphamide in patients with hematologic malignancies." Blood 81, no. 3 (February 1, 1993): 849–55. http://dx.doi.org/10.1182/blood.v81.3.849.849.
Full textAbstract:
Abstract The combination of two powerful immunosuppressive agents, methotrexate (MTX) and cyclosporine (CSP), has resulted in a significant decrease in the morbidity and mortality after allogeneic bone marrow transplantation (BMT). However, the additive toxicities from ablative preparative regimens may lead to suboptimal use of this combined immunoprophylaxis. We evaluated the efficacy and feasibility of administering MTX/CSP with busulfan (4 mg/kg/d for 4 days) and cyclophosphamide (50 mg/kg/d for 4 days) (BuCy4) in 101 consecutive patients with hematologic malignancies categorized into high- and low- risk groups receiving HLA-matched marrow grafts. Postgrafting immunosuppression consisted of MTX short course (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11) and intravenous CSP (1.5 mg/kg every 12 hours). Eighty-three patients (82.1%) received 100% of MTX calculated dose and 87 (86.1%) achieved a CSP therapeutic level (250 to 600 ng/mL) within a median of 16 days. Seventy-three patients (72.2%) received optimal immunosuppressive therapy comprising a full MTX course and achieving CSP therapeutic concentrations. The Kaplan-Meier estimated incidence of grade II to IV acute graft-versus-host disease (GVHD) was 9.2% for all patients and 5.5% in patients receiving optimal GVHD prophylaxis. Eighty-nine patients (88.2%) survived > or = 100 days posttransplant and 43 (48.3%) developed chronic GVHD, the majority of which were de novo (31 of 43). The estimated incidence of relapse was 28.9% for all patients and 14.8% in the low-risk group, with a median follow-up of 24.5 months. High-risk features and the absence of chronic GVHD were significantly associated with relapse (P = .002 and .036, respectively) in multivariate analyses. Projected disease-free survival at 2 years was 52.3% for all patients and 65.2% in low-risk patients. Disease-free survival was significantly improved in optimally treated patients (P = .03) due to a lower incidence of early deaths from acute GVHD and infectious episodes. In conclusion, optimal delivery of MTX/CSP in association with BuCy4 resulted in a near complete abrogation of acute GVHD in HLA-matched transplants and a significantly improved disease-free survival.