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Sample records for allogenic stem cells

  1. Relapse after allogeneic stem cell transplantation

    PubMed Central

    Barrett, A John; Battiwalla, Minoo

    2012-01-01

    Since allogeneic stem cell transplantation (SCT) represents an intensive curative treatment for high-risk malignancies, its failure to prevent relapse leaves few options for successful salvage treatment. While many patients have a high early mortality from relapse, some respond and have sustained remissions, and a minority has a second chance of cure with appropriate therapy. The prognosis for relapsed hematological malignancies after SCT depends on four factors: the time elapsed from SCT to relapse (with relapses occurring within 6 months having the worst prognosis), the disease type (with chronic leukemias and some lymphomas having a second possibility of cure with further treatment), the disease burden and site of relapse (with better treatment success if disease is treated early), and the conditions of the first transplant (with superior outcome for patients where there is an opportunity to increase either the alloimmune effect, the specificity of the antileukemia effect with targeted agents or the intensity of the conditioning in a second transplant). These features direct treatments toward either modified second transplants, chemotherapy, targeted antileukemia therapy, immunotherapy or palliative care. PMID:21083034

  2. Systematic Nutritional Support in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

    PubMed

    Fuji, Shigeo; Einsele, Hermann; Savani, Bipin N; Kapp, Markus

    2015-10-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) has become an established treatment modality for various hematological diseases. However, in allogeneic HSCT, patients often suffer from severe gastrointestinal complications caused by the conditioning regimen and acute/chronic graft-versus-host disease, which requires support by multidisciplinary nutritional support teams (NST). In addition, pretransplantation nutritional status can affect the clinical outcome after allogeneic HSCT. Therefore, it is important to refer the patient to a NST when becoming aware of nutritional problems before allogeneic HSCT. It is also important to follow nutritional status over the long term, as patients often suffer from various nutritional problems, such as malnutrition and metabolic syndrome, even late after allogeneic HSCT. In summary, NST can contribute to the improvement of nutritional status and possibly prognosis at every stage before and after allogeneic HSCT. Here, we aim to give a comprehensive overview of current understanding about nutritional support in allogeneic HSCT and try to provoke a constructive discussion to stimulate further investigation.

  3. Actinomycosis after allogeneic hematopoietic stem cell transplantation despite penicillin prophylaxis.

    PubMed

    Barraco, F; Labussière-Wallet, H; Valour, F; Ducastelle-Leprêtre, S; Nicolini, F-E; Thomas, X; Ferry, T; Dumitrescu, O; Michallet, M; Ader, F

    2016-08-01

    Actinomycosis is a rare chronic and multifaceted disease caused by Actinomyces species frequently mimicking malignancy or other chronic granulomatous lung diseases. We report 4 original presentations of actinomycosis arising under supposed penicillin prophylaxis in allogeneic stem cell transplantation recipients. PMID:27203624

  4. Cellular therapy following allogeneic stem-cell transplantation

    PubMed Central

    Rager, Alison

    2011-01-01

    Allogeneic hematopoietic stem-cell transplantation (HSCT) is the most effective approach for many patients with hematologic malignancies. Unfortunately, relapse remains the most common cause of death after allogeneic HSCT, and the prognosis of relapsed disease is poor for most patients. Induction of a graft-versus-leukemia (GVL), or graft-versus-tumor, effect through the use of donor leukocyte infusion (DLI), or donor lymphocyte infusion, has been remarkably successful for relapsed chronic myelogenous leukemia. Unfortunately, response to DLI in other hematologic malignancies is much less common and depends on many factors including histology, pace and extent of relapse, and time from HSCT to relapse. Furthermore, graft-versus-host disease (GVHD) is common after DLI and often limits successful immunotherapy. Ultimately, manipulations to minimize GVHD while preserving or enhancing GVL are necessary to improve outcomes for relapse after allogeneic HSCT. PMID:23556106

  5. Aspergillus Thyroiditis after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ataca, Pinar; Atilla, Erden; Saracoglu, Pelin; Yilmaz, Gulden; Civriz Bozdag, Sinem; Toprak, Selami Kocak; Yuksel, Meltem Kurt; Ceyhan, Koray; Topcuoglu, Pervin

    2015-01-01

    Aspergillus thyroiditis is a rare disorder detected in immunocompromised patients during disseminated infections. Early management is essential to prevent high mortality. A 61-year-old allogeneic stem cell male recipient presented with painful thyroid nodular enlargement. He had low TSH and low free T4 levels. The thyroid ultrasound showed a hypoechoic nodule; biopsy indicated suppurative Aspergillus thyroiditis. He was successfully treated by amphotericin B. PMID:26640727

  6. New frontiers in pediatric allogeneic stem cell transplantation

    PubMed Central

    Talano, Julie-An M.; Pulsipher, Michael A.; Symons, Heather J.; Militano, Olga; Shereck, Evan B.; Giller, Roger H.; Hancock, Laura; Morris, Erin; Cairo, Mitchell S.

    2015-01-01

    The inaugural meeting of “New Frontiers in Pediatric Allogeneic Stem Cell Transplantation” organized by the Pediatric Blood and Transplant Consortium (PBMTC) was held at the American Society of Pediatric Hematology and Oncology Annual Meeting. This meeting provided an international platform for physicians and investigators active in the research and utilization of pediatric allogeneic stem cell transplantation (AlloSCT) in children and adolescents with malignant and non-malignant disease, to share information and develop future collaborative strategies. The primary objectives of the conference included: 1) to present advances in AlloSCT in pediatric ALL and novel pre- and post-immunotherapy; 2) to highlight new strategies in alternative allogeneic stem cell donor sources for children and adolescents with non-malignant hematological disorders; 3) to discuss timing of immune reconstitution after AlloSCT and methods of facilitating more rapid recovery of immunity; 4) to identify strategies of utilizing AlloSCT in pediatric myeloproliferative disorders (MPD); 5) to develop diagnostic and therapeutic approaches to hematological complications post pediatric AlloSCT; 6) to enhance the understanding of new novel cellular therapeutic approaches to pediatric malignant and non-malignant hematological disorders; and 7) to discuss optimizing drug therapy in pediatric recipients of AlloSCT. This paper will provide a brief overview of the conference. PMID:24820213

  7. Allogenic banking of dental pulp stem cells for innovative therapeutics.

    PubMed

    Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

    2015-08-26

    Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.

  8. Allogenic banking of dental pulp stem cells for innovative therapeutics

    PubMed Central

    Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

    2015-01-01

    Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat. PMID:26328017

  9. SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Fernandes, Sandra; Brooks, Robert; Gumbleton, Matthew; Park, Mi-Young; Russo, Christopher M.; Howard, Kyle T.; Chisholm, John D.; Kerr, William G.

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize autologous and allogeneic HSCT. PMID:26052545

  10. Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

    ClinicalTrials.gov

    2016-04-26

    Thalassemia; Sickle Cell Disease; Glanzmann Thrombasthenia; Wiskott-Aldrich Syndrome; Chronic-granulomatous Disease; Severe Congenital Neutropenia; Leukocyte Adhesion Deficiency; Schwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Fanconi Anemia; Dyskeratosis-congenita; Chediak-Higashi Syndrome; Severe Aplastic Anemia

  11. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses.

    PubMed

    Owens, Sean D; Kol, Amir; Walker, Naomi J; Borjesson, Dori L

    2016-01-01

    Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs) injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM) or adipose tissue derived MSCs (ad-MSCs) were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89%) were positive for anti-bovine serum albumin (BSA) antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection. PMID:27648075

  12. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

    PubMed Central

    2016-01-01

    Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs) injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM) or adipose tissue derived MSCs (ad-MSCs) were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89%) were positive for anti-bovine serum albumin (BSA) antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection. PMID:27648075

  13. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

    PubMed Central

    2016-01-01

    Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs) injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM) or adipose tissue derived MSCs (ad-MSCs) were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89%) were positive for anti-bovine serum albumin (BSA) antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection.

  14. Twisting immune responses for allogeneic stem cell therapy

    PubMed Central

    Li, Shengwen Calvin; Zhong, Jiang F

    2009-01-01

    Stem cell-derived tissues and organs have the potential to change modern clinical science. However, rejection of allogeneic grafts by the host’s immune system is an issue which needs to be addressed before embryonic stem cell-derived cells or tissues can be used as medicines. Mismatches in human leukocyte class I antigens and minor histocompatibility antigens are the central factors that are responsible for various graft-versus-host diseases. Traditional strategies usually involve suppressing the whole immune systems with drugs. There are many side effects associated with these methods. Here, we discuss an emerging strategy for manipulating the central immune tolerance by naturally “introducing” donor antigens to a host so a recipient can acquire tolerance specifically to the donor cells or tissues. This strategy has two distinct stages. The first stage restores the thymic function of adult patients with sex steroid inhibitory drugs (LHRH-A), keratinocyte growth factor (KGF), interleukin 7 (IL-7) and FMS-like tyrosine kinase 3 (FLT3). The second stage introduces hematopoietic stem cells and their downstream progenitors to the restored thymus by direct injection. Hematopoietic stem cells are used to introduce donor antigens because they have priority access to the thymus. We also review several clinical cases to explain this new strategy. PMID:20975985

  15. Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

    PubMed Central

    Muscogiuri, Giovanna; Palomba, Stefano; Serio, Bianca; Sessa, Mariarosaria; Giudice, Valentina; Ferrara, Idalucia; Tauchmanovà, Libuse; Colao, Annamaria; Selleri, Carmine

    2014-01-01

    Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT. PMID:24883377

  16. Endocrinopathies after allogeneic and autologous transplantation of hematopoietic stem cells.

    PubMed

    Orio, Francesco; Muscogiuri, Giovanna; Palomba, Stefano; Serio, Bianca; Sessa, Mariarosaria; Giudice, Valentina; Ferrara, Idalucia; Tauchmanovà, Libuse; Colao, Annamaria; Selleri, Carmine

    2014-01-01

    Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90-99% of women and 60-90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40-50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT. PMID:24883377

  17. Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kato, Keisuke; Koike, Kazutoshi; Kobayashi, Chie; Iijima, Shigeruko; Hashimoto, Takashi; Tsuchida, Masahiro

    2015-06-01

    Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated-donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft-versus-tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT. PMID:26113316

  18. Allogeneic hematopoietic stem cell transplantation for Leukocyte Adhesion Deficiency

    PubMed Central

    Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E.Graham; Davis, Jeffery; Duval, Michel; Eames, Gretchen; Farinha, Nuno; Filopovich, Alexandra; Fischer, Alain; Friedrich, Wilhelm; Gennery, Andrew; Heilmann, Carsten; Landais, Paul; Horwitz, Mitchell; Porta, Fulvio; Sedlacek, Petr; Seger, Reinhard; Slatter, Mary; Teague, Lochie; Eapen, Mary; Veys, Paul

    2012-01-01

    OBJECTIVES Leukocyte Adhesion Deficiency (LAD) is a rare primary immune disorder caused by defects of the CD18 β-integrin molecule on immune cells. The condition usually presents in early infancy and is characterised by deep tissue infections, leukocytosis with impaired formation of pus and delayed wound healing. Allogeneic haematopoietic stem cell transplantation (HSCT) offers the possibility of curative therapy, and with patient numbers at any individual centre being limited, we surveyed the transplant experience at 14 centres worldwide. PATIENTS & METHODS The course of 36 children with a confirmed diagnosis of LAD who underwent HSCT between 1993 and 2007 was retrospectively analysed. Data was collected by the registries of the European Society for Immunodeficiencies (ESID)/European Group for Blood and Marrow Transplantation (EBMT), and the Center for International Blood and Marrow Transplant Research (CIBMTR) RESULTS At median followup of 62 months (extending to 14 years) overall survival was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced intensity conditioning (RIC) in 8 patients, with no deaths in this subgroup. Survival after matched family donor and unrelated donor transplants was similar, with 11/14 matched family donor and 12/14 unrelated donor recipients alive; mortality was greatest following haplo-identical transplants, where 4/8 children did not survive. Twenty seven transplant recipients are alive, with full donor engraftment in 17 cases, mixed multi-lineage chimerism in 7 patients, and mononuclear cell restricted chimerism in a further 3 cases. CONCLUSIONS HSCT offers long term benefit in LAD and should be considered as an early therapeutic option if a suitable HLA-matched stem cell donation is available. Reduced intensity conditioning was particularly safe, and mixed donor chimersim appears sufficient to prevent significant symptoms, although careful long term monitoring will be required for these patients. PMID

  19. [Human Herpesvirus-6 Encephalitis in Allogeneic Hematopoietic Stem Cell Transplantation].

    PubMed

    Ogata, Masao

    2015-07-01

    The reactivation of human herpesvirus-6B (HHV-6B) is common after allogeneic hematopoietic cell transplantation (allo-HCT), and it is sporadically associated with the development of HHV-6 encephalitis. HHV-6 encephalitis typically develops around 2-6 weeks after allo-HCT, and it is characterized by short-term memory loss. Magnetic resonance imaging typically shows bilateral signal abnormalities in the limbic system. The incidence of HHV-6 encephalitis is reportedly 0-11.6% after bone marrow or peripheral blood stem cell transplantation and 4.9-21.4% after cord blood transplantation. The mortality of HHV-6 encephalitis is high, and survivors are often left with serious sequelae. Antiviral therapy using foscarnet or ganciclovir is recommended for the treatment of HHV-6 encephalitis, but the efficacy of the currently available treatment is insufficient once HHV-6 encephalitis has developed. The elucidation of the pathogenesis of HHV-6 encephalitis and the establishment of preventative therapy are needed to overcome this disease.

  20. Allogeneic and autologous mode of stem cell transplantation in regenerative medicine: which way to go?

    PubMed

    Mamidi, Murali Krishna; Dutta, Susmita; Bhonde, Ramesh; Das, Anjan Kumar; Pal, Rajarshi

    2014-12-01

    Stem cell transplantation is a generic term covering different techniques. However there is argument over the pros and cons of autologous and allogeneic transplants of mesenchymal stem cells (MSCs) for regenerative therapy. Given that the MSCs have already been proven to be safe in patients, we hypothesize that allogeneic transplantation could be more effective and cost-effective as compared to autologous transplantation specifically in older subjects who are the likely victims of degenerative diseases. This analysis is based on the scientific logic that allogeneic stem cells extracted in large numbers from young and healthy donors could be physiologically, metabolically and genetically more stable. Therefore stem cells from young donors may be expected to exhibit higher vigor in secreting trophic factors leading to activation of host tissue-specific stem cells and also be more efficient in remodeling the micro-environmental niche of damaged tissue.

  1. Psychosocial adjustment of pediatric patients after allogeneic stem cell transplantation.

    PubMed

    Felder-Puig, R; Peters, C; Matthes-Martin, S; Lamche, M; Felsberger, C; Gadner, H; Topf, R

    1999-07-01

    The purpose of this study was to assess the psychosocial adjustment of patients who had been treated with allogeneic stem cell transplantation (SCT) in our clinic. Selection criteria for patients were to be aged 14-30 years at the time of the follow-up, to be at least 2 years post-SCT and to have a very good knowledge of German. Among 31 eligible patients, 26 participated (84% response rate). The patients were between 15 and 27 years old and were on average 7 years (range 2-13) post-SCT. Research instruments consisted of a demographic questionnaire and various subscales of established psychological measures for which data from a sample of bone cancer survivors and population norms were available. About 35% of patients showed high levels of anxiety, 62% appeared to be extremely sensitive and vulnerable, and 35% showed strong, unfulfilled needs in their love lives. In the other domains tested (self-esteem, family and peer relationships, school/vocational performance, etc), no noticeable differences were found between the subjects and comparable populations. There was no significant association between psychosocial outcome and demographic features or clinical data. Our results suggest that patients who underwent SCT in their childhood or adolescence are at risk of developing long-term emotional or social problems. Due to the retrospective design of our study and the small sample size, no predictive factors for psychosocial distress could be identified.

  2. Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management.

    PubMed

    Griffith, Michelle L; Savani, Bipin N; Boord, Jeffrey B

    2010-08-26

    Currently, approximately 15,000 to 20,000 patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) annually throughout the world, with the number of long-term survivors increasing rapidly. In long-term follow-up after transplantation, the focus of care moves beyond cure of the original disease to the identification and treatment of late effects after HSCT. One of the more serious complications is therapy-related cardiovascular disease. Long-term survivors after HSCT probably have an increased risk of premature cardiovascular events. Cardiovascular complications related to dyslipidemia and other risk factors account for a significant proportion of late nonrelapse morbidity and mortality. This review addresses the risk and causes of dyslipidemia and impact on cardiovascular complications after HSCT. Immunosuppressive therapy, chronic graft-versus-host disease, and other long-term complications influence the management of dyslipidemia. There are currently no established guidelines for evaluation and management of dyslipidemia in HSCT patients; in this review, we have summarized our suggested approach in the HSCT population.

  3. Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

    PubMed Central

    Bensinger, William I.

    2007-01-01

    Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. PMID:18070719

  4. Osteogenic activity of bone marrow-derived mesenchymal stem cells (BMSCs) seeded on irradiated allogenic bone.

    PubMed

    Tohma, Yasuaki; Dohi, Yoshiko; Ohgushi, Hajime; Tadokoro, Mika; Akahane, Manabu; Tanaka, Yasuhito

    2012-02-01

    Allogenic bone grafting, a technique used in orthopaedic surgery, has several problems, including low osteogenic activity. To overcome the problem, this study aimed to determine whether in vivo osteogenesis could be enhanced using allogenic irradiated bone grafts after seeding with autologous bone marrow-derived mesenchymal stem cells (BMSCs). The allogenic bone cylinders were extracted from ACI rats and sterilized by irradiation. Donor BMSCs were obtained from fresh Fischer 344 (F344) rat bone marrow by cell culture. The allogenic bone with or without BMSCs were transplanted subcutaneously into syngeneic F344 rats. At 4 weeks after transplantation, high alkaline phosphatase (ALP) activity, bone-specific osteocalcin mRNA expression and newly formed bone were detected in the allogenic bone with BMSCs. The origin of the newly formed bone was derived from cultured donor BMSCs. However, none of these identifiers of osteogenesis were detected in either the fresh or the irradiated allogenic bone without BMSCs. These results indicate the availability of autologous BMSCs to heighten the osteogenic response of allogenic bone. Our present tissue-engineering method might contribute to a wide variety of allogenic bone grafting techniques in clinical settings.

  5. Regenerative stromal cell therapy in allogeneic hematopoietic stem cell transplantation: Current impact and future directions

    PubMed Central

    Auletta, Jeffery J.; Cooke, Kenneth R.; Solchaga, Luis A.; Deans, Robert J.; Hof, Wouter van’t

    2014-01-01

    Regenerative stromal cell therapy (RSCT) has the potential to become a novel therapy for preventing and treating acute graft-versus-host disease (GVHD) in the allogeneic hematopoietic stem cell transplant (HSCT) recipient. However, enthusiasm for using RSCT in allogeneic HSCT has been tempered by limited clinical data and poorly-defined in vivo mechanisms of action. As a result, the full clinical potential of RSCT in supporting hematopoietic reconstitution and as treatment for GVHD remains to be determined. This manuscript reviews the immunomodulatory activity of regenerative stromal cells in pre-clinical models of allogeneic HSCT and emphasizes an emerging literature suggesting that microenvironment influences RSC activation and function. Understanding this key finding may ultimately define the proper niche for RSCT in allogeneic HSCT. In particular, mechanistic studies are needed to delineate the in vivo effects of RSCT in response to inflammation and injury associated with allogeneic HSCT and to define the relevant sites of RSC interaction with immune cells in the transplant recipient. Furthermore, development of in vivo imaging technology to correlate biodistribution patterns, desired RSC effect, and clinical outcome will be crucial to establishing dose-response effects and minimal biologic-dose thresholds needed to advance translational treatment strategies for complications like GVHD. PMID:20018250

  6. [Single nucleotide polymorphism and its application in allogeneic hematopoietic stem cell transplantation--review].

    PubMed

    Li, Su-Xia

    2004-12-01

    Single nucleotide polymorphism (SNP) is the third genetic marker after restriction fragment length polymorphism (RFLP) and short tandem repeat. It represents the most density genetic variability in the human genome and has been widely used in gene location, cloning, and research of heredity variation, as well as parenthood identification in forensic medicine. As steady heredity polymorphism, single nucleotide polymorphism is becoming the focus of attention in monitoring chimerism and minimal residual disease in the patients after allogeneic hematopoietic stem cell transplantation. The article reviews SNP heredity characterization, analysis techniques and its applications in allogeneic stem cell transplantation and other fields.

  7. Allogeneic Hematopoietic Stem Cell Transplantation in Mantle Cell Lymphoma: A Retrospective Analysis of 7 Patients.

    PubMed

    Lamm, Wolfgang; Wohlfarth, Philipp; Bojic, Marija; Schörgenhofer, Christian; Kalhs, Peter; Raderer, Markus; Rabitsch, Werner

    2015-01-01

    Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma characterized by a poor prognosis. Many different therapeutic approaches including intensive chemotherapy as well as new targeted therapies are established. However, overall survival remains unsatisfying. As the sole curative option, allogeneic hematopoietic stem cell transplantation (HSCT) has been described, but only a limited number of patients qualify for this procedure. We have retrospectively analyzed 7 patients with stage IV MCL undergoing allogeneic HSCT at our institution. A myeloablative regimen was used in 1 patient, while the other 6 patients received reduced-intensity conditioning. Four patients had an HLA-identical sibling, and the remaining 3 patients had an HLA-identical unrelated donor. One patient developed acute graft-versus-host disease (skin, grade III; intestine, grade II). Two patients died from transplant-related causes, 3 patients died due to progressive disease and the remaining 2 patients are still in complete remission 147 and 8 months after transplantation. Allogeneic HSCT offers a therapeutic treatment option for selected patients in a relapsed/refractory setting. The incorporation of novel agents has improved the outcome of patients with MCL. Thus, the role and optimal time point of allogeneic HSCT should be reevaluated in randomized trials.

  8. Functional Reconstitution of Natural Killer Cells in Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ullah, Md Ashik; Hill, Geoffrey R.; Tey, Siok-Keen

    2016-01-01

    Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are important in mediating immunity against both leukemia and pathogens. Although NK cell numbers generally reconstitute within a month, the acquisition of mature NK cell phenotype and full functional competency can take 6 months or more, and is influenced by graft composition, concurrent pharmacologic immunosuppression, graft-versus-host disease, and other clinical factors. In addition, cytomegalovirus infection and reactivation have a dominant effect on NK cell memory imprinting following allogeneic HSCT just as it does in healthy individuals. Our understanding of NK cell education and licensing has evolved in the years since the “missing self” hypothesis for NK-mediated graft-versus-leukemia effect was first put forward. For example, we now know that NK cell “re-education” can occur, and that unlicensed NK cells can be more protective than licensed NK cells in certain settings, thus raising new questions about how best to harness graft-versus-leukemia effect. Here, we review current understanding of the functional reconstitution of NK cells and NK cell education following allogeneic HSCT, highlighting a conceptual framework for future research. PMID:27148263

  9. A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation.

    PubMed

    Brennan, Yvonne; Gottlieb, David J; Baewer, David; Blyth, Emily

    2015-11-01

    Human herpesvirus 6 (HHV-6) is an ubiquitous virus that can reactivate in immunocompromised hosts, resulting in diverse clinical sequelae. We describe a case of fatal acute HHV-6 myocarditis in a patient who underwent allogeneic haemopoietic stem cell transplantation (HSCT). To our knowledge, this is the first reported case of biopsy proven HHV-6 myocarditis post-HSCT.

  10. Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

    PubMed Central

    2010-01-01

    Cellular therapy for spinal cord injury (SCI) is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI. PMID:21070647

  11. Early establishment of hematopoietic chimerism following allogeneic peripheral blood stem cell transplantation in comparison with allogeneic bone marrow transplantation.

    PubMed

    Nakao, S; Zeng, W; Yamazaki, H; Wang, H; Takami, A; Sugimori, N; Miura, Y; Shiobara, S; Matsuda, T; Shinagawa, Y; Harada, M

    1999-04-01

    To characterize the process of the establishment of complete chimerism after allogeneic peripheral blood stem cell transplantation (allo-PBSCT), we determined the origin of leukocytes in peripheral blood (PB) obtained from 23 patients in the very early period after allo-PBSCT using amplification of mini- or microsatellite regions of genomic DNA. Donor-specific alleles were amplified from the PB obtained at day 8 post-transplant for 19 allo-PBSCT patients. Among the 19 patients, 12 showed only donor-specific alleles (complete chimerism) while 7 did both donor and host-specific alleles (mixed chimerism). Although donor specific alleles were amplified in 10 of 12 patients who received allogeneic bone marrow transplantation (allo-BMT) similarly to allo-PBSCT, all of these ten showed mixed chimerism. When the chimeric state was examined in PB samples obtained serially at 2-3-day intervals post-transplant, host-specific alleles in allo-PBSCT patients were not detectable in the PB much earlier than those in allo-BMT patients. These findings indicate that the appearance of donor-derived cells associated with the disappearance of host-derived cells in the circulation occurs earlier after allo-PBSCT as compared with allo-BMT, leading to the rapid establishment of complete chimerism.

  12. Allogeneic adipose-derived stem cells promote survival of fat grafts in immunocompetent diabetic rats.

    PubMed

    Zhang, Jun; Bai, Xiaozhi; Zhao, Bin; Wang, Yunchuan; Su, Linlin; Chang, Peng; Wang, Xujie; Han, Shichao; Gao, Jianxin; Hu, Xiaolong; Hu, Dahai; Liu, Xiaoyan

    2016-05-01

    Autologous adipose-derived stem cells (ADSCs) can protect fat grafts in cell-assisted lipotransfer (CAL). However, diabetes alters the intrinsic properties of ADSCs and impairs their function so that they lack these protective effects. We investigate whether allogeneic ADSCs from healthy donors could protect fat grafts in immunocompetent diabetic rats. Syngeniec adipose tissues and ADSCs were derived from diabetic Lewis (LEW) rats, whereas allogeneic ADSCs were from healthy brown-Norway rats. A grafted mixture containing 0.7 ml granule fat and 0.3 ml 6 × 10(6) allogeneic/syngeneic ADSCs was injected subcutaneously on the skulls of diabetic LEW rats. Fat samples were harvested to evaluate the levels of injury and vascularization as shown by perilipin A, CD34 and VEGF at 14 days. The immune response was evaluated with a lymphocytotoxicity test and the CD4/CD8 ratio in peripheral blood at 14 days. The volume retention of fat grafts was measured at 3 months. Healthy allogeneic ADSCs increased the expression levels of perilipin A, CD34 and VEGF at 14 days. The volume retention of fat grafts was improved by allogeneic ADSCs at 3 months. ADSCs were demonstrated to have low immunogenicity by the lymphocyte proliferation test and immunophenotype including MHC and co-stimulatory markers. The lymphocytotoxicity test and CD4/CD8 ratio indicated no obvious immune response elicited by allogeneic ADSCs. Thus, healthy allogeneic ADSCs can promote the survival of fat grafts in this immunocompetent diabetic rat model, with little or no obvious immune rejection.

  13. Allogenous tendon stem/progenitor cells in silk scaffold for functional shoulder repair.

    PubMed

    Shen, Weiliang; Chen, Jialin; Yin, Zi; Chen, Xiao; Liu, Huanhuan; Heng, Boon Chin; Chen, Weishan; Ouyang, Hong-Wei

    2012-01-01

    Tendon stem/progenitor cells (TSPCs) were recently identified within tendon tissues. The aim of this study was to investigate TSPC-seeded knitted silk-collagen sponge scaffold for functional shoulder repair. The multidifferentiation potential, proliferation, and immune properties of TSPCs were investigated in vitro, while the efficacy of TSPC-seeded knitted silk-collagen sponge scaffolds in promoting rotator cuff regeneration was evaluated in vivo within a rabbit model. TSPCs, which exhibited universal stem cell characteristics (i.e., clonogenicity, high proliferative capacity, and multidifferentiation potential), nonimmunogenicity, and immunosuppression, proliferated well on our scaffold in vitro. Implantation of allogenous TSPC-seeded scaffolds within a rabbit rotator cuff injury model did not elicit an immunological reaction, but instead increased fibroblastic cell ingrowth and reduced infiltration of lymphocytes within the implantation sites at 4 and 8 weeks postsurgery. After 12 weeks, the allogenous TSPC-treated group exhibited increased collagen deposition and had better structural and biomechanical properties compared to the control group. This study thus demonstrated that the allogenous TSPC-seeded knitted silk-collagen sponge scaffold enhanced the efficacy of rotator cuff tendon regeneration by differentiating into tenocytes, and by secreting anti-inflammatory cytokines that prevent immunological rejection. Hence, allogenous TSPC-seeded knitted silk-collagen sponge scaffolds can be a clinically useful application for tendon tissue engineering.

  14. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient. PMID:25674158

  15. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient.

  16. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency

    PubMed Central

    Cuellar-Rodriguez, Jennifer; Gea-Banacloche, Juan; Freeman, Alexandra F.; Hsu, Amy P.; Zerbe, Christa S.; Calvo, Katherine R.; Wilder, Jennifer; Kurlander, Roger; Olivier, Kenneth N.; Holland, Steven M.

    2011-01-01

    We performed nonmyeloablative HSCT in 6 patients with a newly described genetic immunodeficiency syndrome caused by mutations in GATA2—a disease characterized by nontuberculous mycobacterial infection, monocytopenia, B- and NK-cell deficiency, and the propensity to transform to myelodysplastic syndrome/acute myelogenous leukemia. Two patients received peripheral blood stem cells (PBSCs) from matched-related donors, 2 received PBSCs from matched-unrelated donors, and 2 received stem cells from umbilical cord blood (UCB) donors. Recipients of matched-related and -unrelated donors received fludarabine and 200 cGy of total body irradiation (TBI); UCB recipients received cyclophosphamide in addition to fludarabine and TBI as conditioning. All patients received tacrolimus and sirolimus posttransplantation. Five patients were alive at a median follow-up of 17.4 months (range, 10-25). All patients achieved high levels of donor engraftment in the hematopoietic compartments that were deficient pretransplantation. Adverse events consisted of delayed engraftment in the recipient of a single UCB, GVHD in 4 patients, and immune-mediated pancytopenia and nephrotic syndrome in the recipient of a double UCB transplantation. Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B-cell, and NK-cell populations and reversal of the clinical phenotype. Registered at www.clinicaltrials.gov as NCT00923364. PMID:21816832

  17. Reconstruction of Beagle Hemi-Mandibular Defects with Allogenic Mandibular Scaffolds and Autologous Mesenchymal Stem Cells

    PubMed Central

    Luo, JinChao; Liu, HuaWei; Hu, Min; Yue, Wen

    2014-01-01

    Objective Massive bone allografts are frequently used in orthopedic reconstructive surgery, but carry a high failure rate of approximately 25%. We tested whether treatment of graft with mesenchymal stem cells (MSCs) can increase the integration of massive allografts (hemi-mandible) in a large animal model. Methods Thirty beagle dogs received surgical left-sided hemi-mandibular defects, and then divided into two equal groups. Bony defects of the control group were reconstructed using allografts only. Those of the experimental group were reconstructed using allogenic mandibular scaffold-loaded autologous MSCs. Beagles from each group were killed at4 (n = 4), 12 (n = 4), 24 (n = 4) or 48 weeks (n = 3) postoperatively. CT and micro-CT scans, histological analyses and the bone mineral density (BMD) of transplants were used to evaluate defect reconstruction outcomes. Results Gross and CT examinations showed that the autologous bone grafts had healed in both groups. At 48 weeks, the allogenic mandibular scaffolds of the experimental group had been completely replaced by new bone, which has a smaller surface area to that of the original allogenic scaffold, whereas the scaffold in control dogs remained the same size as the original allogenic scaffold throughout. At 12 weeks, the BMD of the experimental group was significantly higher than the control group (p<0.05), and all micro-architectural parameters were significantly different between groups (p<0.05). Histological analyses showed almost all transplanted allogeneic bone was replaced by new bone, principally fibrous ossification, in the experimental group, which differed from the control group where little new bone formed. Conclusions Our study demonstrated the feasibility of MSC-loaded allogenic mandibular scaffolds for the reconstruction of hemi-mandibular defects. Further studies are needed to test whether these results can be surpassed by the use of allogenic mandibular scaffolds loaded with a

  18. Prophylaxis and treatment of acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Chen, Runzhe; Campbell, Jos L; Chen, Baoan

    2015-01-01

    Relapse of acute lymphoblastic leukemia remains a major cause of death in patients following allogeneic hematopoietic stem cell transplantation. Several factors may affect the concurrence and outcome of relapse, which include graft-versus-host disease, minimal residual disease or intrinsic factors of the disease, and transplantation characteristics. The mainstay of relapse prevention and treatment is donor leukocyte infusions, targeted therapies, second transplantation, and other novel therapies. In this review, we mainly focus on addressing the impact of graft-versus-host disease on relapse and the prophylaxis and treatment of acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation. We also make recommendations for critical strategies to prevent relapse after transplantation and challenges that must be addressed to ensure success. PMID:25709473

  19. Fungemia Caused by Zygoascus hellenicus in an Allogeneic Stem Cell Transplant Recipient

    PubMed Central

    Brandt, Mary E.; Kauffman, Carol A.; Pappas, Peter G.; Iqbal, Naureen; Arthington-Skaggs, Beth A.; Lee-Yang, Wendy; Smith, Maudy T.

    2004-01-01

    Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast. PMID:15243118

  20. Voriconazole-Induced Periostitis Mimicking Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation.

    PubMed

    Sweiss, Karen; Oh, Annie; Rondelli, Damiano; Patel, Pritesh

    2016-01-01

    Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy.

  1. Voriconazole-Induced Periostitis Mimicking Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

    PubMed Central

    Oh, Annie; Rondelli, Damiano; Patel, Pritesh

    2016-01-01

    Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy. PMID:27403356

  2. Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Björklund, Andreas T; Clancy, Trevor; Goodridge, Jodie P; Béziat, Vivien; Schaffer, Marie; Hovig, Eivind; Ljunggren, Hans-Gustaf; Ljungman, Per T; Malmberg, Karl-Johan

    2016-02-01

    Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high-resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56(bright), NKG2A(+), NKG2C(+), and CD57(+) NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A(+)CD57(-)NKG2C(-)) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03-0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9-12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6-33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1-77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9-12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7-11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12-0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01-0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT. PMID:26746188

  3. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL). PMID:27000734

  4. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  5. Peripheral blood CD5-positive B lymphocytes (B-1a cells) after allogeneic stem cell transplantation for acute myeloid leukaemia in humans

    PubMed Central

    Veneri, Dino; Franchini, Massimo; de Sabata, Donata; Ledro, Silvia; Vella, Antonio; Ortolani, Riccardo; Pizzolo, Giovanni; Benedetti, Fabio

    2008-01-01

    Background Only few data are available in literature regarding the reconstitution of B-1a cells after allogeneic bone marrow transplantation performed for haematological malignancies. Methods In this study we used flow cytometry to assess the reconstitution of the peripheral blood B-1a cell compartment after allogeneic peripheral blood stem cell transplantation. Cytometric analyses were performed over time on 11 consecutive patients undergoing allogeneic peripheral blood stem cell transplantation for acute myeloid leukaemia in our Haematology Unit and the results were compared with available data regarding B-1a cell reconstitution after allogeneic bone marrow stem cell transplantation. Results In spite of an earlier recovery of B-1a cells in the peripheral blood after allogeneic bone marrow transplantation, the reconstitution of this B-cell subset was similar, regardless of the source of stem cells employed. Conclusions Further studies are necessary in order to clarify the origin of B-1a cells in humans in health and illness. PMID:19112737

  6. Cynomolgus Monkey Induced Pluripotent Stem Cells Generated By Using Allogeneic Genes.

    PubMed

    Shimozawa, Nobuhiro

    2016-01-01

    Induced pluripotent stem (iPS) cells that are potentially similar to embryonic stem (ES) cells can be artificially established by introduction into somatic cells of the transgenes POU5F1 (also known as Oct3/4), SOX2, KLF4, and c-MYC. In cynomolgus monkeys (Macaca fascicularis), iPS cells generated by using these four allogeneic transgenes should be an important resource for various types of biomedical research because the use of xenogeneic transgenes may cause complications. To establish such iPS cells, cynomolgus monkey somatic cells were infected with amphotropic retroviral vectors, which were derived from Plat-A cells, containing cDNA for the cynomolgus monkey genes POU5F1, SOX2, KLF4, and c-MYC. As a result, iPS cells could be established from somatic cells from fetal liver and newborn skin of cynomolgus monkeys, similarly to the case for mouse and human somatic cells. PMID:25410287

  7. Allogeneic Mesenchymal Stem Cells in Combination with Hyaluronic Acid for the Treatment of Osteoarthritis in Rabbits.

    PubMed

    Chiang, En-Rung; Ma, Hsiao-Li; Wang, Jung-Pan; Liu, Chien-Lin; Chen, Tain-Hsiung; Hung, Shih-Chieh

    2016-01-01

    Mesenchymal stem cell (MSC)-based therapies may aid in the repair of articular cartilage defects. The purpose of this study was to investigate the effects of intraarticular injection of allogeneic MSCs in an in vivo anterior cruciate ligament transection (ACLT) model of osteoarthritis in rabbits. Allogeneic bone marrow-derived MSCs were isolated and cultured under hypoxia (1% O2). After 8 weeks following ACLT, MSCs suspended in hyaluronic acid (HA) were injected into the knees, and the contralateral knees were injected with HA alone. Additional controls consisted of a sham operation group as well as an untreated osteoarthritis group. The tissues were analyzed by macroscopic examination as well as histologic and immunohistochemical methods at 6 and 12 weeks post-transplantation. At 6 and 12 weeks, the joint surface showed less cartilage loss and surface abrasion after MSC injection as compared to the tissues receiving HA injection alone. Significantly better histological scores and cartilage content were observed with the MSC transplantation. Furthermore, engraftment of allogenic MSCs were evident in surface cartilage. Thus, injection of the allogeneic MSCs reduced the progression of osteoarthritis in vivo.

  8. Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome

    PubMed Central

    Alessandrino, Emilio Paolo; Porta, Matteo G Della; Malcovati, Luca; Jackson, Christopher H; Pascutto, Cristiana; Bacigalupo, Andrea; Teresa van Lint, Maria; Falda, Michele; Bernardi, Massimo; Onida, Francesco; Guidi, Stefano; Iori, Anna Paola; Cerretti, Raffaella; Marenco, Paola; Pioltelli, Pietro; Angelucci, Emanuele; Oneto, Rosi; Ripamonti, Francesco; Rambaldi, Alessandro; Bosi, Alberto; Cazzola, Mario

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Am. J. Hematol. 88:581–588, 2013. © 2013 Wiley Periodicals, Inc. PMID:23606215

  9. Allogeneic Mesenchymal Stem Cells in Combination with Hyaluronic Acid for the Treatment of Osteoarthritis in Rabbits

    PubMed Central

    Chiang, En-Rung; Ma, Hsiao-Li; Wang, Jung-Pan; Liu, Chien-Lin; Chen, Tain-Hsiung; Hung, Shih-Chieh

    2016-01-01

    Mesenchymal stem cell (MSC)-based therapies may aid in the repair of articular cartilage defects. The purpose of this study was to investigate the effects of intraarticular injection of allogeneic MSCs in an in vivo anterior cruciate ligament transection (ACLT) model of osteoarthritis in rabbits. Allogeneic bone marrow-derived MSCs were isolated and cultured under hypoxia (1% O2). After 8 weeks following ACLT, MSCs suspended in hyaluronic acid (HA) were injected into the knees, and the contralateral knees were injected with HA alone. Additional controls consisted of a sham operation group as well as an untreated osteoarthritis group. The tissues were analyzed by macroscopic examination as well as histologic and immunohistochemical methods at 6 and 12 weeks post-transplantation. At 6 and 12 weeks, the joint surface showed less cartilage loss and surface abrasion after MSC injection as compared to the tissues receiving HA injection alone. Significantly better histological scores and cartilage content were observed with the MSC transplantation. Furthermore, engraftment of allogenic MSCs were evident in surface cartilage. Thus, injection of the allogeneic MSCs reduced the progression of osteoarthritis in vivo. PMID:26915044

  10. Characteristics of mouse adipose tissue-derived stem cells and therapeutic comparisons between syngeneic and allogeneic adipose tissue-derived stem cell transplantation in experimental autoimmune thyroiditis.

    PubMed

    Choi, Eun Wha; Shin, Il Seob; Park, So Young; Yoon, Eun Ji; Kang, Sung Keun; Ra, Jeong Chan; Hong, Sung Hwa

    2014-01-01

    Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic) or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissue-derived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations.

  11. A problem-solving education intervention in caregivers and patients during allogeneic hematopoietic stem cell transplantation.

    PubMed

    Bevans, Margaret; Wehrlen, Leslie; Castro, Kathleen; Prince, Patricia; Shelburne, Nonniekaye; Soeken, Karen; Zabora, James; Wallen, Gwenyth R

    2014-05-01

    The aim of this study was to determine the effect of problem-solving education on self-efficacy and distress in informal caregivers of allogeneic hematopoietic stem cell transplantation patients. Patient/caregiver teams attended three 1-hour problem-solving education sessions to help cope with problems during hematopoietic stem cell transplantation. Primary measures included the Cancer Self-Efficacy Scale-transplant and Brief Symptom Inventory-18. Active caregivers reported improvements in self-efficacy (p < 0.05) and distress (p < 0.01) post-problem-solving education; caregiver responders also reported better health outcomes such as fatigue. The effect of problem-solving education on self-efficacy and distress in hematopoietic stem cell transplantation caregivers supports its inclusion in future interventions to meet the multifaceted needs of this population.

  12. Investigation of allogeneic mesenchymal stem cell-based alveolar bone formation: preliminary findings.

    PubMed

    De Kok, Ingeborg J; Peter, Susan J; Archambault, Michael; van den Bos, Christian; Kadiyala, Sudha; Aukhil, Ikramuddin; Cooper, Lyndon F

    2003-08-01

    This study was designed to evaluate mesenchymal stem cell (MSC)-based alveolar bone regeneration in a canine alveolar saddle defect model. MSCs were loaded onto hydroxyapatite/tricalcium phosphate (HA/TCP) matrices. Scanning electron microscopic (SEM) evaluation demonstrated greater than 75% MSC coverage of the HA/TCP porous surface prior to placement regardless of MSC donor. Matrices, 6 mm x 6 mm x 20 mm, with and without cells, were implanted for 4 and 9 weeks, then removed for histological evaluation of bone formation. Cell-free control matrices were compared with MSC-loaded matrices post implantation. Histomorphometrical analysis showed that equivalent amounts of new bone were formed within the pores of the matrices loaded with autologous MSCs or MSCs from an unrelated donor. Bone formation in the cell-free HA/TCP matrices was less extensive. There was no histologic evidence of an immunological response to autologous MSCs. Surprisingly, allogeneic MSC implantation also failed to provoke an immune response. Analysis of circulating antibody levels against MSCs supported the hypothesis that neither autologous nor allogeneic MSCs induced a systemic response by the host. Analysis of dye-labelled MSCs in histological sections confirmed that the MSCs persisted in the implants throughout the course of the experiment. At 9 weeks, labelled cells were present within the lacunae of newly formed bone. We conclude that autologous and allogeneic MSCs have the capacity to regenerate bone within craniofacial defects.

  13. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation

    PubMed Central

    Goldberg, Jenna D.; Yuan, Jianda; Koehne, Guenther; Lechner, Lauren; Papadopoulos, Esperanza B.; Young, James W.; Jakubowski, Ann A.; Zaidi, Bushra; Gallardo, Humilidad; Liu, Cailian; Rasalan, Teresa; Wolchok, Jedd D.; Croughs, Therese; Morre, Michel; Devlin, Sean M.; van den Brink, Marcel R. M.

    2012-01-01

    Delays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and relapse. IL-7 has a central role in T-cell development and survival and enhances immune recovery in murine models of allo-HSCT. We performed a phase 1 trial of r-hIL-7 (CYT107) in recipients of T-cell depleted allo-HSCTs. Twelve patients were treated with escalating doses of r-hIL-7 administered weekly for 3 weeks. The study drug was well tolerated with only one patient developing acute skin GVHD. At baseline, patients were profoundly lymphopenic. CYT107 induced a doubling in CD4+ and CD8+ T cells. The main effect of IL-7 was an expansion of effector memory T cells, the predominant subset identified in our patients. There was no significant effect on CD4+CD25+FoxP3+ T cells, NK, or B cells. Importantly, we not only saw quantitative increases in T cells after a short course of IL-7 but also demonstrated an increase in functional T cells, including viral-specific T cells that recognize CMV. Enhanced TCR diversity was also observed after treatment. Our results indicate that r-hIL-7 can enhance immune recovery after a T cell–depleted allo-HSCT without causing significant GVHD or other serious toxicity (www.clinicaltrials.gov; NCT00684008). PMID:23012326

  14. Some aspects of allogeneic stem cell transplantation in patients with myelodysplastic syndrome: advances and controversy

    PubMed Central

    Blau, Olga; Blau, Igor Wolfgang

    2014-01-01

    Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorders. MDS remains a disease of elderly patients; moreover, the incidence of high risk MDS is proportionally greater in elderly patients, with increased frequency of secondary acute myeloid leukemia, as well as adverse cytogenetic abnormalities. Allogeneic stem cell transplantation is a therapeutic approach with known curative potential for patients with MDS that allows the achievement of long-term disease control. Numerous controversies still exist regarding transplantation in MDS: timing of transplantation, disease status at transplantation and comorbidity, conditioning intensity, pretransplant therapy, and stem cell source. Various transplant modalities of different intensities and alternative donor sources are now in use. Current advances in transplant technology are allowing the consideration of older patients. This should result in a greater number of older patients benefiting from this potentially curative treatment modality. Despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reduced early mortality, transplant numbers in MDS patients have significantly increased. Moreover, recent new developments with innovative drugs, including hypomethylating agents, have extended the therapeutic alternatives for MDS patients. Hypomethylating agents allow the delay of allogeneic stem cell transplantation by serving as an effective and well-tolerated means to reduce disease burden. PMID:25506229

  15. Iodine-131-metaiodobenzylguanidine therapy with reduced-intensity allogeneic stem cell transplantation in recurrent neuroblastoma.

    PubMed

    Takahashi, Hiroka; Manabe, Atsushi; Aoyama, Chiaki; Kamiya, Takahiro; Kato, Itaru; Takusagawa, Ayako; Ogawa, Chitose; Ozawa, Miwa; Hosoya, Ryota; Yokoyama, Kunihiko

    2008-03-01

    Neuroblastoma is the most common extracranial solid tumor of childhood, and iodine-131-metaiodobenzylguanidine (MIBG) therapy is a new approach for grade IV neuroblastoma. We describe the case history of a 3-year-old girl with recurrent neuroblastoma who received MIBG therapy with reduced-intensity allogeneic stem cell transplantation (RIST) because of an extensive bone marrow involvement. The post-transplant course was uneventful and complete chimerism was obtained. Neither acute nor chronic graft-versus-host disease (GVHD) was observed. The patient remained in remission for 3 months after RIST until the second relapse. MIBG therapy combined with RIST warrants further trials.

  16. Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mishra, Asmita; Anasetti, Claudio

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population. PMID:27521324

  17. Optimal stem cell source for allogeneic stem cell transplantation for hematological malignancies

    PubMed Central

    Cheuk, Daniel KL

    2013-01-01

    Hematopoietic stem cell transplant (HSCT) is a standard treatment for many hematological malignancies. Three different sources of stem cells, namely bone marrow (BM), peripheral blood stem cells (PBSC) and cord blood (CB) can be used for HSCT, and each has its own advantages and disadvantages. Randomized controlled trials (RCTs) suggest that there is no significant survival advantage of PBSC over BM in Human Leukocyte Antigen-matched sibling transplant for adult patients with hematological malignancies. PBSC transplant probably results in lower risk of relapse and hence better disease-free survival, especially in patients with high risk disease at the expense of higher risks of both severe acute and chronic graft-versus-host disease (GVHD). In the unrelated donor setting, the only RCT available suggests that PBSC and BM result in comparable overall and disease-free survivals in patients with hematological malignancies; and PBSC transplant results in lower risk of graft failure and higher risk of chronic GVHD. High level evidence is not available for CB in comparison to BM or PBSC. The risks and benefits of different sources of stem cells likely change with different conditioning regimen, strategies for prophylaxis and treatment of GVHD and manipulation of grafts. The recent success and rapid advance of double CB transplant and haploidentical BM and PBSC transplants further complicate the selection of stem cell source. Optimal selection requires careful weighing of the risks and benefits of different stem cell source for each individual recipient and donor. Detailed counseling of patient and donor regarding risks and benefits in the specific context of the patient and transplant method is essential for informed decision making. PMID:24392314

  18. The Role of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation for Hodgkin Lymphoma

    PubMed Central

    Holmberg, Leona; Maloney, David G.

    2011-01-01

    Patients with Hodgkin lymphoma are usually cured by primary therapy using chemotherapy alone or combined modality therapy with external beam radiation. Patients who do not experience a complete remission or those who experience relapse may by salvaged by high-dose therapy and autologous hematopoietic stem cell transplantation (ASCT). Success of this approach is largely dependent on the tumor being sensitive to salvage chemotherapy before transplant. More studies are showing the predictive value of functional imaging in this setting. Allogeneic hematopoietic stem cell transplantation has greater risk of nonrelapse mortality and is generally reserved for patients who experience relapse post-ASCT, but may provide long-term survival for some patients through graft-versus-tumor immune effects. PMID:21917627

  19. Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients

    PubMed Central

    Hobbs, Gabriela Soriano; Perales, Miguel-Angel

    2015-01-01

    Graft versus host disease (GVHD) remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT). The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients with AML in first complete remission, CD34+ selected grafts afford overall and relapse-free survival comparable to those observed in recipients of conventional grafts, while significantly decreasing GVHD. In addition, CD34+ selected grafts allow older patients, and those with medical comorbidities or with only HLA-mismatched donors to successfully undergo transplantation. Prospective data are needed to further define which groups of patients with AML are most likely to benefit from CD34+ selected grafts. Here we review the history of T-cell depletion in AML, and techniques used. We then summarize the contemporary literature using CD34+ selection in recipients of matched or partially mismatched donors (7/8 or 8/8 HLA-matched), and provide a summary of the risks and benefits of using T-cell depletion. PMID:26239251

  20. Donor CD4 T Cell Diversity Determines Virus Reactivation in Patients After HLA-Matched Allogeneic Stem Cell Transplantation

    PubMed Central

    Ritter, J; Seitz, V; Balzer, H; Gary, R; Lenze, D; Moi, S; Pasemann, S; Seegebarth, A; Wurdack, M; Hennig, S; Gerbitz, A; Hummel, M

    2015-01-01

    Delayed reconstitution of the T cell compartment in recipients of allogeneic stem cell grafts is associated with an increase of reactivation of latent viruses. Thereby, the transplanted T cell repertoire appears to be one of the factors that affect T cell reconstitution. Therefore, we studied the T cell receptor beta (TCRβ) gene rearrangements of flow cytometry–sorted CD4+ and CD8+ T cells from the peripheral blood of 23 allogeneic donors before G-CSF administration and on the day of apheresis. For this purpose, TCRβ rearrangements were amplified by multiplex PCR followed by high-throughput amplicon sequencing. Overall, CD4+ T cells displayed a significantly higher TCRβ diversity compared to CD8+ T cells irrespective of G-CSF administration. In line, no significant impact of G-CSF treatment on the TCR Vβ repertoire usage was found. However, correlation of the donor T cell repertoire with clinical outcomes of the recipient revealed that a higher CD4+ TCRβ diversity after G-CSF treatment is associated with lower reactivation of cytomegalovirus and Epstein–Barr virus. By contrast, no protecting correlation was observed for CD8+ T cells. In essence, our deep TCRβ analysis identifies the importance of the CD4+ T cell compartment for the control of latent viruses after allogeneic stem cell transplantation. PMID:25873100

  1. Systemic Administration of Allogeneic Mesenchymal Stem Cells Does Not Halt Osteoporotic Bone Loss in Ovariectomized Rats

    PubMed Central

    Sun, Yuxin; Lin, Sien; Gu, Weidong; Liu, Yamei; Zhang, Jinfang; Chen, Lin; Li, Gang

    2016-01-01

    Mesenchymal stem cells (MSCs) have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1) Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2) Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX) rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX) and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91). Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn’t show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study

  2. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Szyska, Martin; Na, Il-Kang

    2016-01-01

    The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians. PMID:27066008

  3. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study

    PubMed Central

    Ferreira, Érika Elias; Guerra, Daiane Cristina; Baluz, Kátia; de Resende Furtado, Wander; da Silva Bouzas, Luis Fernando

    2014-01-01

    Objective This study aimed to describe and compare the nutritional status of adult patients submitted to allogeneic hematopoietic stem cell transplantation at two different time points (admission and discharge). Methods A retrospective, descriptive and quantitative study was performed based on clinical, laboratory and nutritional data obtained from medical records of adult patients of both genders submitted to allogeneic hematopoietic stem cell transplantation in a bone marrow transplantation reference center in Rio de Janeiro in the period from 2010 to 2013. Statistical analysis was performed using the SPSS software (version 22.0). Results Sixty-four patients were evaluated. The mean age was 42.1 ± 3.2 years and the most prevalent disease was acute myeloid leukemia (39%). There was a high prevalence of gastrointestinal symptoms including nausea (100%), vomiting (97%) and mucositis (93%). Between admission and discharge there was a significant decrease in the median weight (−2.5 kg; 71.5 vs. 68.75 kg; p-value < 0.001), body mass index (−0.9 kg/m2; 24.8 vs. 24.4 kg/m2; p-value < 0.001), and serum albumin levels (−0.2 g/dL; 3.7 vs. 3.6 g/dL; p-value = 0.024). The survival time after hematopoietic stem cell transplantation correlated negatively with C-reactive protein at discharge (CC = −0.72; p-value < 0.001) and positively with serum albumin levels (CC = 0.56; p-value = 0.004) and with high total protein level at discharge (CC = 0.53; p-value = 0.006). Conclusion Our results suggest that patients submitted to allogeneic hematopoietic stem cell transplantation have compromised nutritional status during the hospital stay for transplantation. PMID:25453651

  4. Chimerism of bone marrow mesenchymal stem/stromal cells in allogeneic hematopoietic cell transplantation: is it clinically relevant?

    PubMed

    Miura, Yasuo; Yoshioka, Satoshi; Yao, Hisayuki; Takaori-Kondo, Akifumi; Maekawa, Taira; Ichinohe, Tatsuo

    2013-01-01

    Multipotent mesenchymal stem/stromal cells (MSCs) have been extensively used as a transplantable cell source for regenerative medicine and immunomodulatory therapy. Specifically in allogeneic hematopoietic stem cell transplantation (HSCT), co-transplantation or post-transplant infusion of MSCs derived from bone marrow (BM) of non-self donors has been implicated in accelerating hematopoietic recovery, ameliorating graft-vs.-host disease, and promoting tissue regeneration. However, irrespective of the use of MSC co-administration, post-transplant chimerism of BM-derived MSCs after allogeneic HSCT has been reported to remain of host origin, suggesting that the infused donor MSCs are immunologically rejected or not capable of long-term engraftment in the host microenvironment. Also, hematopoietic cell allografts currently used for HSCT do not seem to contain sufficient amount of MSCs or their precursors to reconstitute host BM microenvironment. Since the toxic conditioning employed in allo-HSCT may impair the function of host MSCs to maintain hematopoietic/regenerative stem cell niches and to provide a local immunomodulatory milieu, we propose that new directions for enhancing immunohematopoietic reconstitution and tissue repair after allogeneic HSCT include the development of strategies to support functional replenishment of residual host MSCs or to support more efficient engraftment of infused donor MSCs. Future areas of research should include in vivo tracking of infused MSCs and detection of their microchimeric presence in extra-marrow sites as well as in BM.

  5. Digital PCR to assess hematopoietic chimerism after allogeneic stem cell transplantation.

    PubMed

    Stahl, Tanja; Böhme, Manja U; Kröger, Nicolaus; Fehse, Boris

    2015-06-01

    Analysis of hematopoietic chimerism after allogeneic stem cell transplantation represents a crucial method to evaluate donor-cell engraftment. Whereas sensitivity of classical approaches for chimerism monitoring is limited to ≥1%, quantitative polymerase chain reaction (qPCR)-based techniques readily detect one patient cell in >1,000 donor cells, thus facilitating application of chimerism assessment as a surrogate for minimal residual disease. However, due to methodologic specificities, qPCR combines its high sensitivity with limited resolution power in the state of mixed chimerism (e.g., >10% patient cells). Our aim was to overcome this limitation by employing a further development of qPCR, namely digital PCR (dPCR), for chimerism analysis. For proof-of-principle, we established more than 10 dPCR assays detecting Indel polymorphisms or Y-chromosome sequences and tested them on artificial cell mixtures and patient samples. Employing artificial cell mixtures, we found that dPCR allows exact quantification of chimerism over several orders of magnitude. Digital PCR results proved to be highly reproducible (deviation <5%), particularly in the "difficult" range of mixed chimerism. Excellent performance of the new assays was confirmed by analysis of multiple retrospective blood samples from patients after allogeneic stem cell transplantation, in comparison with established qPCR (14 patients) and short-tandem repeat PCR (4 patients) techniques. Finally, dPCR is easy to perform, needs only small amounts of DNA for chimerism assessment (65 ng corresponds to a sensitivity of approximately 0.03%), and does not require the use of standard curves and replicate analysis. In conclusion, dPCR represents a very promising method for routine chimerism monitoring.

  6. Efficacy of immune suppression tapering in treating relapse after reduced intensity allogeneic stem cell transplantation.

    PubMed

    Kekre, Natasha; Kim, Haesook T; Thanarajasingam, Gita; Armand, Philippe; Antin, Joseph H; Cutler, Corey; Nikiforow, Sarah; Ho, Vincent T; Koreth, John; Alyea, Edwin P; Soiffer, Robert J

    2015-09-01

    For patients who relapse after allogeneic hematopoietic stem cell transplantation while still on immune suppression, there is anecdotal evidence that tapering the immune suppression may result in graft-versus-tumor activity. We reviewed the medical records of all patients with documented histological or radiographic disease recurrence within 1 year of stem cell transplantation while on immune suppression at our institution. The median time to relapse was 110 days (range, 18-311) after transplant. Among 123 patients with relapse treated with immune suppression tapering without chemotherapy, radiation, or donor lymphocyte infusion, 34 responded (33/101 reduced intensity conditioning transplant and 1/22 myeloablative conditioning transplant, 32.7% and 4.5% respectively; P=0.007). The median time to response after initiation of immune suppression tapering was 82 days (range, 16-189). Thirty-three patients (97.1%) had development or progression of acute or chronic graft-versus-host disease as a consequence of immune suppression tapering, at a median time of 39 days (range, 16-98). Six patients subsequently relapsed late after initial response to immune suppression tapering at a median time of 2 years (range, 0.9-3.8). The median overall survival from immune suppression tapering for responders was 5.1 years (range, 1.9-not estimable). When clinically feasible, immune suppression tapering alone in patients who relapse early after reduced intensity conditioning allogeneic stem cell transplantation can produce durable remissions, but is almost always associated with graft-versus-host disease.

  7. Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

    PubMed

    Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

    2005-03-01

    Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure. PMID:15522953

  8. [Effect of decitabine on immune regulation in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

    PubMed

    Wang, Jing; Zhou, Jin; Zheng, Hui-Fei; Fu, Zheng-Zheng

    2014-10-01

    Based on the representative articles in recent years, the different mechanisms of decitabine on immune regulation in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) are summarized. Decitabine improves the expression of WT1 gene to stimulate specific cytotoxic T cells which can enhance graft versus leukemia effect (GVL) and improve the expression of FOXP3 gene to stimulate regulatory T cells so as to inhibit the acute graft versus host disease (GVHD). Through the above-mentimed mechanisms, decitabine can improve both therapeutic effect and quality of life in the patients with AML after allogeneic HSCT.

  9. Induction with azacytidine followed by allogeneic hematopoietic stem cell transplantation in a Jehovah's Witness with acute monocytic leukemia

    PubMed Central

    Garelius, Hege; Grund, Sofia; Stockelberg, Dick

    2015-01-01

    Key Clinical Message We have used a hypomethylating agent instead of conventional chemotherapy to induce remission in a young Jehovah's Witness with acute monocytic leukemia to avoid severe myelosuppression and blood product support. The treatment was consolidated with reduced intensity allogeneic stem cell transplantation. This could be an alternative when transfusions must be avoided. PMID:25984306

  10. Induction with azacytidine followed by allogeneic hematopoietic stem cell transplantation in a Jehovah's Witness with acute monocytic leukemia.

    PubMed

    Garelius, Hege; Grund, Sofia; Stockelberg, Dick

    2015-05-01

    We have used a hypomethylating agent instead of conventional chemotherapy to induce remission in a young Jehovah's Witness with acute monocytic leukemia to avoid severe myelosuppression and blood product support. The treatment was consolidated with reduced intensity allogeneic stem cell transplantation. This could be an alternative when transfusions must be avoided. PMID:25984306

  11. Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation.

    PubMed

    Robin, Frédéric; Paillard, Catherine; Marchandin, Hélène; Demeocq, François; Bonnet, Richard; Hennequin, Claire

    2010-11-01

    We report a case of meningitis due to Lactobacillus rhamnosus in a child undergoing allogeneic hematopoietic stem cell transplantation for acute leukemia. Four episodes of bacteremia involving strains with pulsotypes identical to that of the cerebrospinal fluid isolate preceded meningitis. After several courses of clindamycin, no relapse occurred during the patient follow-up.

  12. Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models

    PubMed Central

    Li, Ya-jun; Zhao, Bao-lin; Lv, Hao-ze; Qin, Zhi-gang; Luo, Min

    2016-01-01

    We hypothesized that a chemically extracted acellular allogeneic nerve graft used in combination with bone marrow mesenchymal stem cell transplantation would be an effective treatment for long-segment sciatic nerve defects. To test this, we established rabbit models of 30 mm sciatic nerve defects, and treated them using either an autograft or a chemically decellularized allogeneic nerve graft with or without simultaneous transplantation of bone marrow mesenchymal stem cells. We compared the tensile properties, electrophysiological function and morphology of the damaged nerve in each group. Sciatic nerves repaired by the allogeneic nerve graft combined with stem cell transplantation showed better recovery than those repaired by the acellular allogeneic nerve graft alone, and produced similar results to those observed with the autograft. These findings confirm that a chemically extracted acellular allogeneic nerve graft combined with transplantation of bone marrow mesenchymal stem cells is an effective method of repairing long-segment sciatic nerve defects. PMID:27651781

  13. Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models

    PubMed Central

    Li, Ya-jun; Zhao, Bao-lin; Lv, Hao-ze; Qin, Zhi-gang; Luo, Min

    2016-01-01

    We hypothesized that a chemically extracted acellular allogeneic nerve graft used in combination with bone marrow mesenchymal stem cell transplantation would be an effective treatment for long-segment sciatic nerve defects. To test this, we established rabbit models of 30 mm sciatic nerve defects, and treated them using either an autograft or a chemically decellularized allogeneic nerve graft with or without simultaneous transplantation of bone marrow mesenchymal stem cells. We compared the tensile properties, electrophysiological function and morphology of the damaged nerve in each group. Sciatic nerves repaired by the allogeneic nerve graft combined with stem cell transplantation showed better recovery than those repaired by the acellular allogeneic nerve graft alone, and produced similar results to those observed with the autograft. These findings confirm that a chemically extracted acellular allogeneic nerve graft combined with transplantation of bone marrow mesenchymal stem cells is an effective method of repairing long-segment sciatic nerve defects.

  14. Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient.

    PubMed

    Osthoff, M; Chew, E; Bajel, A; Kelsey, G; Panek-Hudson, Y; Mason, K; Szer, J; Ritchie, D; Slavin, M

    2013-02-01

    Toxoplasmosis is increasingly diagnosed after hematopoietic stem cell transplantation (HSCT) and is associated with considerable morbidity and mortality. In the majority of cases, reactivation of latent disease secondary to impaired cellular and humoral immunity after HSCT is believed to be the main pathogenetic mechanism. Hence, primary toxoplasmosis is rarely considered in the differential diagnosis of infections after HSCT in a recipient who is seronegative for Toxoplasma gondii pre-transplant. We herein report a seronegative patient with acute T-cell lymphoblastic leukemia, who developed primary disseminated toxoplasmosis 5 months after HSCT from a seronegative unrelated donor. A review of all reported cases of primary toxoplasmosis after HSCT revealed significantly increased morbidity and mortality. Patients with negative pre-transplant Toxoplasma serology should therefore be considered at risk for toxoplasmosis after allogeneic HSCT. Possible prevention and monitoring strategies for seronegative recipients are reviewed and discussed in detail.

  15. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678. PMID:25587040

  16. New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia.

    PubMed

    Tadokoro, Mika; Kanai, Rie; Taketani, Takeshi; Uchio, Yuji; Yamaguchi, Seiji; Ohgushi, Hajime

    2009-06-01

    Mesenchymal stem cells (MSCs) can show osteogenic differentiation capability when implanted in vivo, as well as cultured in vitro; therefore we attempted to use allogeneic MSCs for an 8-month-old patient with hypophosphatasia. MSCs were obtained by culture expansion of fresh marrow from the patient's father. Some of the MSCs were further cultured under osteogenic conditions on a culture dish or porous hydroxyapatite ceramics, resulting in cultured osteoblasts and osteogenic constructs, respectively. The MSCs and osteoblasts were injected into the patient, and the constructs were implanted locally. After traditional bone marrow transplantation, the MSCs, osteoblasts, and osteogenic constructs were used for treatment and to improve the patient's respiratory condition and skeletal abnormality. The condition worsened again, and an MSC booster shot was administered. At the same time, the construct was retrieved. The respiratory condition improved, and the retrieved construct showed de novo bone derived from both donor and patient cells. We demonstrated the importance of allogeneic MSC transplantation for hypophosphatasia and the constructs as an alternative to bone fragments that provided further osteogenic capability in the patient. PMID:19446101

  17. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

  18. Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction

    PubMed Central

    Kraitchman, Dara L.; Tatsumi, Mitsuaki; Gilson, Wesley D.; Ishimori, Takayoshi; Kedziorek, Dorota; Walczak, Piotr; Paul Segars, W.; Chen, Hunter H.; Fritzges, Danielle; Izbudak, Izlem; Young, Randell G.; Marcelino, Michelle; Pittenger, Mark F.; Solaiyappan, Meiyappan; Boston, Raymond C.; Tsui, Benjamin M.W.; Wahl, Richard L.; Bulte, Jeff W.M.

    2005-01-01

    Background Recent results from animal studies suggest that stem cells may be able to home to sites of myocardial injury to assist in tissue regeneration. However, the histological interpretation of postmortem tissue, on which many of these studies are based, has recently been widely debated. Methods and Results With the use of the high sensitivity of a combined single-photon emission CT (SPECT)/CT scanner, the in vivo trafficking of allogeneic mesenchymal stem cells (MSCs) colabeled with a radiotracer and MR contrast agent to acute myocardial infarction was dynamically determined. Redistribution of the labeled MSCs after intravenous injection from initial localization in the lungs to nontarget organs such as the liver, kidney, and spleen was observed within 24 to 48 hours after injection. Focal and diffuse uptake of MSCs in the infarcted myocardium was already visible in SPECT/CT images in the first 24 hours after injection and persisted until 7 days after injection and was validated by tissue counts of radioactivity. In contrast, MRI was unable to demonstrate targeted cardiac localization of MSCs in part because of the lower sensitivity of MRI. Conclusions Noninvasive radionuclide imaging is well suited to dynamically track the biodistribution and trafficking of mesenchymal stem cells to both target and nontarget organs. PMID:16129797

  19. The Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients

    PubMed Central

    Marini, Bernard L.; Choi, Sung Won; Byersdorfer, Craig Alan; Cronin, Simon; Frame, David G.

    2015-01-01

    As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, become a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. There is also increasing evidence that several anti-hyperlipidemia medications, the HMG-CoA reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published ACC/AHA guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agent’s potential role in modulating GVHD. PMID:25459644

  20. Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes.

    PubMed

    Yakushijin, K; Atsuta, Y; Doki, N; Yokota, A; Kanamori, H; Miyamoto, T; Ohwada, C; Miyamura, K; Nawa, Y; Kurokawa, M; Mizuno, I; Mori, T; Onizuka, M; Taguchi, J; Ichinohe, T; Yabe, H; Morishima, Y; Kato, K; Suzuki, R; Fukuda, T

    2016-03-01

    This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, -2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival. PMID:26595082

  1. Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study

    PubMed Central

    Azık, Fatih; Gürlek Gökçebay, Dilek; Tavil, Betül; Işık, Pamir; Tunç, Bahattin; Uçkan, Duygu

    2015-01-01

    Objective: Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. Materials and Methods: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including FV G1691A (factor V Leiden), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein (a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. Results: In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. Conclusion: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study. PMID:25912774

  2. Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation

    PubMed Central

    2013-01-01

    Viral infections are important causes of morbidity and mortality after allogeneic stem cell hematopoietic transplantation (allo-HSCT). Although most viral infections present with asymptomatic or subclinical manifestations, viruses may result in fatal complications in severe immunocompromised recipients. Reactivation of latent viruses, such as herpesviruses, is frequent during the immunosuppression that occurs with allo-HSCT. Viruses acquired from community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases. Currently, molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, in diagnosis of viral infections. The utilization of polymerase chain reaction facilitates the early diagnosis. In view of lacking efficacious agents for treatment of viral diseases, prevention of viral infections is extremely valuable. Application of prophylactic strategies including preemptive therapy reduces viral infections and diseases. Adoptive cellular therapy for restoring virus-specific immunity is a promising method in the treatment of viral diseases. PMID:24341630

  3. Treatment of severe post-traumatic bone defects with autologous stem cells loaded on allogeneic scaffolds.

    PubMed

    Vulcano, Ettore; Murena, Luigi; Cherubino, Paolo; Falvo, Daniele A; Rossi, Antonio; Baj, Andreina; Toniolo, Antonio

    2012-12-01

    Mesenchymal stem cells may differentiate into angiogenic and osteoprogenitor cells. The effectiveness of autologous pluripotent mesenchymal cells for treating bone defects has not been investigated in humans. We present a case series to evaluate the rationale of using nucleated cells from autologous bone marrow aspirates in the treatment of severe bone defects that failed to respond to traditional treatments. Ten adult patients (mean age, 49.6-years-old) with severe bone defects were included in this study. Lower limb bone defects were >or=5 cm3 in size, and upper limb defects .or=2 cm3. Before surgery, patients were tested for antibodies to common pathogens. Treatment consisted of bone allogeneic scaffold enriched with bone marrow nucleated cells harvested from the iliac crest and concentrated using an FDA-approved device. Postsurgery clinical and radiographic follow-up was performed at 1, 3, 6, and 12 months. To assess viability, morphology, and immunophenotype, bone marrow nucleated cells were cultured in vitro, tested for sterility, and assayed for the possible replication of adventitious (contaminating) viruses. In 9 of 10 patients, both clinical and radiographic healing of the bone defect along with bone graft integration were observed (mean time, 5.6 months); one patient failed to respond. No post-operative complications were observed. Bone marrow nucleated cells were enriched 4.49-fold by a single concentration step, and these enriched cells were free of microbial contamination. The immunophenotype of adherent cells was compatible with that of mesenchymal stem cells. We detected the replication of Epstein-Barr virus in 2/10 bone marrow cell cultures tested. Hepatitis B virus, cytomegalovirus, parvovirus B19, and endogenous retrovirus HERV-K replication were not detected. Overall, 470 to 1,150 million nucleated cells were grafted into each patient. This case series, with a mean follow-up of almost 2 years, demonstrates that an allogeneic bone scaffold

  4. Risk-adjusted outcome measurement in pediatric allogeneic stem cell transplantation.

    PubMed

    Matthes-Martin, Susanne; Pötschger, Ulrike; Bergmann, Kirsten; Frommlet, Florian; Brannath, Werner; Bauer, Peter; Klingebiel, Thomas

    2008-03-01

    The purpose of the study was to define a risk score for 1-year treatment-related mortality (TRM) in children undergoing allogeneic stem cell transplantation as a basis for risk-adjusted outcome assessment. We analyzed 1364 consecutive stem cell transplants performed in 24 German and Austrian centers between 1998 and 2003. Five well-established risk factors were tested by multivariate logistic regression for predictive power: patient age, disease status, donor other than matched sibling donor, T cell depletion (TCD), and preceding stem cell transplantation. The risk score was defined by rounding the parameter estimates of the significant risk factors to the nearest integer. Crossvalidation was performed on the basis of 5 randomly extracted equal-sized parts from the database. Additionally, the score was validated for different disease entities and for single centers. Multivariate analysis revealed a significant correlation of TRM with 3 risk factors: age >10 years, advanced disease, and alternative donor. The parameter estimates were 0.76 for age, 0.73 for disease status, and 0.97 for donor type. Rounding the estimates resulted in a score with 1 point for each risk factor. One-year TRM (overall survival [OS]) were 5% (89%) with a score of 0, 18% (74%) with 1, 28% (54%) with 2, and 53% (27%) with 3 points. Crossvalidation showed stable results with a good correlation between predicted and observed mortality but moderate discrimination. The score seems to be a simple instrument to estimate the expected mortality for each risk group and for each center. Measuring TRM risk-adjusted and the comparison between expected and observed mortality may be an additional tool for outcome assessment in pediatric stem cell transplantation. PMID:18275900

  5. T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome

    PubMed Central

    Gaballa, Ahmed; Sundin, Mikael; Stikvoort, Arwen; Abumaree, Muhamed; Uzunel, Mehmet; Sairafi, Darius; Uhlin, Michael

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T cells are responsible for both the beneficial graft-versus-leukemia (GVL) effect against malignant cells and protection against infections. The immune recovery of T cells relies initially on peripheral expansion of mature cells from the graft and later on the differentiation and maturation from donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released upon rearrangement of the T cell receptor. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. Here, we discuss the role of TREC analysis in the prediction of clinical outcome after allogeneic HSCT. Due to the pivotal role of T cell reconstitution we propose that TREC analysis should be included as a key indicator in the post-HSCT follow-up. PMID:27727179

  6. Bone marrow-derived hematopoietic stem and progenitor cells infiltrate allogeneic and syngeneic transplants.

    PubMed

    Fan, Z; Enjoji, K; Tigges, J C; Toxavidis, V; Tchipashivili, V; Gong, W; Strom, T B; Koulmanda, M

    2014-12-01

    Lineage (CD3e, CD11b, GR1, B220 and Ly-76) negative hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) infiltrate islet allografts within 24 h posttransplantation. In fact, lineage(negative) Sca-1(+) cKit(+) ("LSK") cells, a classic signature for HSCs, were also detected among these graft infiltrating cells. Lineage negative graft infiltrating cells are functionally multi-potential as determined by a standard competitive bone marrow transplant (BMT) assay. By 3 months post-BMT, both CD45.1 congenic, lineage negative HSCs/HPCs and classic "LSK" HSCs purified from islet allograft infiltrating cells, differentiate and repopulate multiple mature blood cell phenotypes in peripheral blood, lymph nodes, spleen, bone marrow and thymus of CD45.2 hosts. Interestingly, "LSK" HSCs also rapidly infiltrate syngeneic islet transplants as well as allogeneic cardiac transplants and sham surgery sites. It seems likely that an inflammatory response, not an adaptive immune response to allo-antigen, is responsible for the rapid infiltration of islet and cardiac transplants by biologically active HSCs/HPCs. The pattern of hematopoietic differentiation obtained from graft infiltrating HSCs/HPCs, cells that are recovered from inflammatory sites, as noted in the competitive BMT assay, is not precisely the same as that of intramedullary HSCs. This does not refute the obvious multi-lineage potential of graft infiltrating HSCs/HPCs.

  7. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Masouridi-Levrat, Stavroula; Simonetta, Federico; Chalandon, Yves

    2016-01-01

    Bone marrow failure (BMF) syndromes are severe complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this paper, we distinguish two different entities, the graft failure (GF) and the poor graft function (PGF), and we review the current understanding of the interactions between the immune and hematopoietic compartments in these conditions. We first discuss how GF occurs as the result of classical alloreactive immune responses mediated by residual host cellular and humoral immunity persisting after conditioning and prevented by host and donor regulatory T cells. We next summarize the current knowledge about the contribution of inflammatory mediators to the development of PGF. In situations of chronic inflammation complicating allo-HSCT, such as graft-versus-host disease or infections, PGF seems to be essentially the result of a sustained impairment of hematopoietic stem cells (HSC) self-renewal and proliferation caused by inflammatory mediators, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, and of induction of apoptosis through the Fas/Fas ligand pathway. Interestingly, the production of inflammatory molecules leads to a non-MHC restricted, bystander inhibition of hematopoiesis, therefore, representing a promising target for immunological interventions. Finally, we discuss immune-mediated impairment of bone marrow microenvironment as a potential mechanism hampering hematopoietic recovery. Better understanding of immunological mechanisms responsible for BMF syndromes after allo-HSCT may lead to the development of more efficient immunotherapeutic interventions. PMID:27695456

  8. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Masouridi-Levrat, Stavroula; Simonetta, Federico; Chalandon, Yves

    2016-01-01

    Bone marrow failure (BMF) syndromes are severe complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this paper, we distinguish two different entities, the graft failure (GF) and the poor graft function (PGF), and we review the current understanding of the interactions between the immune and hematopoietic compartments in these conditions. We first discuss how GF occurs as the result of classical alloreactive immune responses mediated by residual host cellular and humoral immunity persisting after conditioning and prevented by host and donor regulatory T cells. We next summarize the current knowledge about the contribution of inflammatory mediators to the development of PGF. In situations of chronic inflammation complicating allo-HSCT, such as graft-versus-host disease or infections, PGF seems to be essentially the result of a sustained impairment of hematopoietic stem cells (HSC) self-renewal and proliferation caused by inflammatory mediators, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, and of induction of apoptosis through the Fas/Fas ligand pathway. Interestingly, the production of inflammatory molecules leads to a non-MHC restricted, bystander inhibition of hematopoiesis, therefore, representing a promising target for immunological interventions. Finally, we discuss immune-mediated impairment of bone marrow microenvironment as a potential mechanism hampering hematopoietic recovery. Better understanding of immunological mechanisms responsible for BMF syndromes after allo-HSCT may lead to the development of more efficient immunotherapeutic interventions.

  9. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3-4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  10. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3–4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  11. Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mendorf, Alexander; Klyuchnikov, Evgeny; Langebrake, Claudia; Rohde, Holger; Ayuk, Francis; Regier, Marc; Christopeit, Maximilian; Zabelina, Tatjana; Bacher, Adelbert; Stübig, Thomas; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus

    2015-01-01

    Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials. PMID:25968483

  12. A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Tavakoli Ardakani, Maria; Tafazoli, Ali; Mehdizadeh, Mahshid; Hajifathali, Abbas; Dadashzadeh, Simin

    2016-01-01

    Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy.

  13. Role of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia

    PubMed Central

    Lussana, Federico; Rambaldi, Alessandro

    2014-01-01

    Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease, due to the expression of different biological and clinical risk factors, for which allogeneic stem cell transplantation (alloHSCT) is an effective consolidation therapy. The non-relapse mortality of alloHSCT remains significantly higher compared with that of conventional chemotherapy. Therefore, one of the main challenges in the care of ALL is to establish a more precise prognostic definition to select patients who could take advantage from an alloHSCT. Currently, the use of minimal residual disease following induction and early consolidation therapy has improved the prognostic accuracy in defining ALL risk class. In Philadelphia-positive ALL, the introduction of tyrosine kinase inhibitors pre and post alloHSCT appears to improve outcomes significantly and, in the absence of specially designed clinical trials, alloHSCT remains the most effective post-remission therapy. Nowadays, alloHSCT can be performed according to various modalities encompassing the use of different conditioning regimens, as well as distinct donors and stem cell source, with a significant accessibility to transplant. PMID:25408851

  14. A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Tavakoli Ardakani, Maria; Tafazoli, Ali; Mehdizadeh, Mahshid; Hajifathali, Abbas; Dadashzadeh, Simin

    2016-01-01

    Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy. PMID:27610174

  15. Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mendorf, Alexander; Klyuchnikov, Evgeny; Langebrake, Claudia; Rohde, Holger; Ayuk, Francis; Regier, Marc; Christopeit, Maximilian; Zabelina, Tatjana; Bacher, Adelbert; Stübig, Thomas; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus

    2015-01-01

    Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials.

  16. Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation

    PubMed Central

    Brennan, Todd V.; Lin, Liwen; Huang, Xiaopei; Cardona, Diana M.; Li, Zhiguo; Dredge, Keith; Chao, Nelson J.

    2012-01-01

    Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD. PMID:22760779

  17. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation.

    PubMed

    Ciceri, Fabio; Bonini, Chiara; Marktel, Sarah; Zappone, Elisabetta; Servida, Paolo; Bernardi, Massimo; Pescarollo, Alessandra; Bondanza, Attilio; Peccatori, Jacopo; Rossini, Silvano; Magnani, Zulma; Salomoni, Monica; Benati, Claudia; Ponzoni, Maurilio; Callegaro, Luciano; Corradini, Paolo; Bregni, Marco; Traversari, Catia; Bordignon, Claudio

    2007-06-01

    The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK(+) cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo expansion of TK(+) cells. Seven patients received ganciclovir, resulting in elimination of TK(+) cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK(+) cells in the context of allografting and represent the basis for a broader application of this technology. PMID:17327416

  18. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter?

    PubMed

    Goldman, John; Gordon, Myrtle

    2006-01-01

    It is generally accepted that allogeneic stem cell transplantation can 'cure' chronic myelogenous leukemia (CML), although occasional patients relapse more than 10 years after the transplant procedure. Such cures presumably result from the combined effects of leukemia stem cells (LSCs) of the conditioning regimen and the graft-vs.-leukemia (GvL) effect mediated by donor-derived T lymphocytes. The advent of imatinib has revolutionized the management of patients with CML, but much evidence suggests that it does not eradicate all LSCs, which theoretically remain a potential source of relapse to chronic phase or advanced phase disease. Moreover, sub-clones of Philadelphia-positive cells bearing mutations that code for amino-acid substitutions in the Bcr-Abl kinase domain can be identified in patients receiving treatment with imatinib and are associated with varying degrees of resistance to this agent. In the present review, we postulate that LSCs, similar to their normal counterparts, may alternate between cycling and quiescent modes. In the cycling mode, they may express Bcr-Abl protein and be susceptible to the acquisition of additional mutations, whereas, in the quiescent mode, they may express little or no Bcr-Abl oncoprotein, cannot acquire additional mutations and are unaffected by imatinib. Thus, a patient who starts treatment early in the natural history of CML, and who responds to imatinib clinically, may not have had the opportunity to acquire additional mutations in LSCs. In this case, the persistence long-term of quiescent 'non-mutated' LSCs despite imatinib treatment might be consistent with freedom from relapse to chronic or advanced phase disease, provided that they remain vulnerable to imatinib when they are recruited into cycle. Conversely, when imatinib resistant Philadelphia-positive sub-clones predominate, this is likely to be due to the recruitment to hematopoiesis of quiescent stem cells that had been in cycle before administration of imatinib and

  19. Current Role of Autologous and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

    PubMed Central

    Castagna, Luca; Carlo-Stella, Carmelo; Mazza, Rita; Santoro, Armando

    2015-01-01

    Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States. First-line chemo-radiotherapy leads to cure rates approaching 80% in patients with advanced-stage disease. However, 25 to 30% of these patients are not cured with chemotherapy alone (i.e., the ABVD regimen) and show either primary refractoriness to chemotherapy, early disease relapse or late disease relapse. Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) have an established role in the management of refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients. However, due to the poor responses to second-line salvage chemotherapy and dismal long-term disease control of primary refractory and early relapsed patients, their treatment represents an unmet medical need. Allogeneic SCT represents, by far, the only strategy with a curative potential for these patients; however, as discussed in this review, it’s role in cHL remains controversial. Despite a general consensus that early relapsed and primary refractory patients represent a clinical challenge requiring effective treatments to achieve long-term disease control, there has been no consensus on the optimal therapy that should be offered to these patients. This review will briefly discuss the clinical results and the main issues regarding autologous SCT as well as the current role of allogeneic SCT. PMID:25745542

  20. Late Mortality and Causes of Death among Long-Term Survivors after Allogeneic Stem Cell Transplantation.

    PubMed

    Atsuta, Yoshiko; Hirakawa, Akihiro; Nakasone, Hideki; Kurosawa, Saiko; Oshima, Kumi; Sakai, Rika; Ohashi, Kazuteru; Takahashi, Satoshi; Mori, Takehiko; Ozawa, Yukiyasu; Fukuda, Takahiro; Kanamori, Heiwa; Morishima, Yasuo; Kato, Koji; Yabe, Hiromasa; Sakamaki, Hisashi; Taniguchi, Shuichi; Yamashita, Takuya

    2016-09-01

    We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT; however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up.

  1. Toxoplasmosis after allogeneic stem cell transplantation--a single centre experience.

    PubMed

    Busemann, Christoph; Ribback, Silvia; Zimmermann, Kathrin; Sailer, Verena; Kiefer, Thomas; Schmidt, Christian A; Schulz, Katrin; Steinmetz, Ivo; Dombrowski, Frank; Dölken, Gottfried; Krüger, William H

    2012-07-01

    Toxoplasmosis is a rare but possibly underestimated complication following allogeneic stem cell transplantation with a high mortality rate. One reason might be the limitation of the diagnostic instruments relying mainly on imaging and molecular-based techniques. In this report, we present three cases of toxoplasmosis identified among 155 allograft recipients treated at Greifswald University Hospital. Widely disseminated toxoplasmosis was detected post-mortem in two patients allografted for high-risk multiple myeloma. Clinical signs suspicious for toxoplasmosis occurred after days +32 and +75, respectively. In one case, serology and conventional Toxoplasma gondii PCR, targeting the B1 gene, revealed negative results, while in the other patient, toxoplasmosis was not investigated. Both patients received pentamidine for Pneumocystis jirovecii pneumonia (PcP) prophylaxis. The third patient, a 68-year-old woman allografted for AML, developed cerebral toxoplasmosis from day +395 after allogeneic SCT with typical signs in magnetic resonance tomography. Toxoplasma DNA was amplified from one of two samples of cerebrospinal fluid. The patient died of disseminated toxoplasmosis despite immediate initiation of therapy. Retrospective comparative testing of clinical specimens by the conventional T. gondii PCR and by a real-time PCR targeting a 529-bp genomic fragment suggests a higher sensitivity of the latter method in our patients. In conclusion, we suggest a rigorous real-time PCR monitoring for high-risk patients or patients with signs of infections suspicious for toxoplasmosis, even though low-copy results are presently difficult to interpret. Our reported cases might also encourage the use of trimethoprim-sufmethoxazole instead of pentamidine for PcP prophylaxis in those patients.

  2. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity

    PubMed Central

    Quevedo, Henry C.; Hatzistergos, Konstantinos E.; Oskouei, Behzad N.; Feigenbaum, Gary S.; Rodriguez, Jose E.; Valdes, David; Pattany, Pradip M.; Zambrano, Juan P.; Hu, Qinghua; McNiece, Ian; Heldman, Alan W.; Hare, Joshua M.

    2009-01-01

    The mechanism(s) underlying cardiac reparative effects of bone marrow-derived mesenchymal stem cells (MSC) remain highly controversial. Here we tested the hypothesis that MSCs regenerate chronically infarcted myocardium through mechanisms comprising long-term engraftment and trilineage differentiation. Twelve weeks after myocardial infarction, female swine received catheter-based transendocardial injections of either placebo (n = 4) or male allogeneic MSCs (200 million; n = 6). Animals underwent serial cardiac magnetic resonance imaging, and in vivo cell fate was determined by co-localization of Y-chromosome (Ypos) cells with markers of cardiac, vascular muscle, and endothelial lineages. MSCs engrafted in infarct and border zones and differentiated into cardiomyocytes as ascertained by co-localization with GATA-4, Nkx2.5, and α-sarcomeric actin. In addition, Ypos MSCs exhibited vascular smooth muscle and endothelial cell differentiation, contributing to large and small vessel formation. Infarct size was reduced from 19.3 ± 1.7% to 13.9 ± 2.0% (P < 0.001), and ejection fraction (EF) increased from 35.0 ± 1.7% to 41.3 ± 2.7% (P < 0.05) in MSC but not placebo pigs over 12 weeks. This was accompanied by increases in regional contractility and myocardial blood flow (MBF), particularly in the infarct border zone. Importantly, MSC engraftment correlated with functional recovery in contractility (R = 0.85, P < 0.05) and MBF (R = 0.76, P < 0.01). Together these findings demonstrate long-term MSC survival, engraftment, and trilineage differentiation following transplantation into chronically scarred myocardium. MSCs are an adult stem cell with the capacity for cardiomyogenesis and vasculogenesis which contribute, at least in part, to their ability to repair chronically scarred myocardium. PMID:19666564

  3. Increasing chimerism after allogeneic stem cell transplantation is associated with longer survival time.

    PubMed

    Tang, Xiaowen; Alatrash, Gheath; Ning, Jing; Jakher, Haroon; Stafford, Patricia; Zope, Madhushree; Shpall, Elizabeth J; Jones, Roy B; Champlin, Richard E; Thall, Peter F; Andersson, Borje S

    2014-08-01

    Donor chimerism after allogeneic stem cell transplantation (allo-SCT) is commonly used to predict overall survival (OS) and disease-free survival (DFS). Because chimerism is observed at 1 or more times after allo-SCT and not at baseline, if chimerism is in fact associated with OS or DFS, then the occurrence of either disease progression or death informatively censors (terminates) the observed chimerism process. This violates the assumptions underlying standard statistical regression methods for survival analysis, which may lead to biased conclusions. To assess the association between the longitudinal post-allo-SCT donor chimerism process and OS or DFS, we analyzed data from 195 patients with acute myelogenous leukemia (n = 157) or myelodysplastic syndrome (n = 38) who achieved complete remission after allo-SCT following a reduced-toxicity conditioning regimen of fludarabine/intravenous busulfan. Median follow-up was 31 months (range, 1.1 to 105 months). Fitted joint longitudinal-survival time models showed that a binary indicator of complete (100%) donor chimerism and increasing percent of donor T cells were significantly associated with longer OS, whereas decreasing percent of donor T cells was highly significantly associated with shorter OS. Our analyses illustrate the usefulness of modeling repeated post-allo-SCT chimerism measurements as individual longitudinal processes jointly with OS and DFS to estimate their relationships.

  4. Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

    PubMed Central

    Itzykson, Raphael; Robin, Marie; Moins-Teisserenc, Helene; Delord, Marc; Busson, Marc; Xhaard, Aliénor; de Fontebrune, Flore Sicre; de Latour, Régis Peffault; Toubert, Antoine; Socié, Gérard

    2015-01-01

    Immune reconstitution after allogeneic stem cell transplantation is a dynamic and complex process depending on the recipient and donor characteristics, on the modalities of transplantation, and on the occurrence of graft-versus-host disease. Multivariate methods widely used for gene expression profiling can simultaneously analyze the patterns of a great number of biological variables on a heterogeneous set of patients. Here we use these methods on flow cytometry assessment of up to 25 lymphocyte populations to analyze the global pattern of long-term immune reconstitution after transplantation. Immune patterns were most distinct from healthy controls at six months, and had not yet fully recovered as long as two years after transplant. The two principal determinants of variability were linked to the balance of B and CD8+ T cells and of natural killer and B cells, respectively. Recipient’s cytomegalovirus serostatus, cytomegalovirus replication, and chronic graft-versus-host disease were the main factors shaping the immune pattern one year after transplant. We identified a complex signature of under- and over-representation of immune populations dictated by recipient’s cytomegalovirus seropositivity. Finally, we identified dimensions of variance in immune patterns as significant predictors of long-term non-relapse mortality, independently of chronic graft-versus-host disease. PMID:25261095

  5. Risk-factor analysis of poor graft function after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Xiao, Yang; Song, Jiayin; Jiang, Zujun; Li, Yonghua; Gao, Yang; Xu, Wenning; Lu, Ziyuan; Wang, Yaochun; Xiao, Haowen

    2014-01-01

    The objective of this study was to investigate the main risk factors for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to allow the improvement of transplantation outcomes through preventive measures. Clinical data for 124 patients who received allo-HSCT were analyzed retrospectively. There were 83 males (66.9%) and 41 females (33.1%) with a median age of 28 years (4-60 years). The median follow-up time was 7 months (1-116 months). Factors analyzed included age, gender, disease diagnosis, source of hematopoietic stem cells, donor type, human leukocyte antigen (HLA) matching, conditioning regimen, numbers of infused mononuclear cells and CD34(+) cells, donor-recipient sex and blood-type matching, prophylactic treatment of graft-versus-host disease (GVHD), grades of GVHD, Epstein-Barr virus or cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorders and hepatic veno-occlusive disease. Data were analyzed by univariate and multivariate conditional logistic regression analyses. Among the 124 patients who underwent allo-HSCT, 15 developed PGF (12.1%). Univariate logistic regression analysis identified age, donor-recipient blood type and CMV infection (in 30 days) as potential risk factors for PGF. Multivariate analysis of factors with P<0.1 in univariate analysis showed that age, donor-recipient blood type and CMV infection (in 30 days) were significant risk factors for PGF. Patients were divided into subgroups based on age <20, 20-30, 30-40, and >40 years. The risk of PGF increased 2.747-fold (odds ratio (OR)=2.625, 95% confidence interval: 1.411-5.347) for each increment in age level. Patients with mismatched blood type (OR=4.051) or CMV infection (OR=9.146) had an increased risk of PGF. We conclude that age, donor-recipient blood-type matching and CMV infection are major risk factors for PGF after allo-HSCT.

  6. Autoantibodies against glutamate receptor δ2 after allogenic stem cell transplantation

    PubMed Central

    Miske, Ramona; Hahn, Stefanie; Rosenkranz, Thorsten; Müller, Matthias; Dettmann, Inga M.; Mindorf, Swantje; Denno, Yvonne; Brakopp, Stefanie; Scharf, Madeleine; Teegen, Bianca; Probst, Christian; Melzer, Nico; Meinck, Hans-Michael; Terborg, Christoph; Stöcker, Winfried

    2016-01-01

    Objective: To report on a Caucasian patient who developed steroid-responsive transverse myelitis, graft vs host disease of the gut, and anti-GluRδ2 after allogenic stem cell transplantation. Methods: Histoimmunoprecipitation (HIP) with the patient's serum and cryosections of rat and porcine cerebellum followed by mass spectrometry was used to identify the autoantigen. Correct identification was verified by indirect immunofluorescence using recombinant GluRδ2 expressed in HEK293 cells. Results: The patient's serum produced a granular staining of the cerebellar molecular layer (immunoglobulin G1 and immunoglobulin G3; endpoint titer: 1:1,000) but did not react with other CNS tissues or 28 established recombinant neural autoantigens. HIP revealed a unique protein band at ∼110 kDa that was identified as GluRδ2. The patient's serum also stained GluRδ2 transfected but not mock-transfected HEK293 cells. Control sera from 38 patients with multiple sclerosis, 85 patients with other neural autoantibodies, and 205 healthy blood donors were negative for anti-GluRδ2. Preadsorption with lysate from HEK293-GluRδ2 neutralized the patient's tissue reaction whereas control lysate had no effect. In addition to anti-GluRδ2, the patient's serum contained immunoglobulin G autoantibodies against the pancreatic glycoprotein CUZD1, which are known to be markers of Crohn disease. Conclusions: In the present case, the development of anti-GluRδ2 was associated with transverse myelitis, which was supposedly triggered by the stem cell transplantation. Similar to encephalitis in conjunction with anti-GluRδ2 reported in a few Japanese patients, the patient's neurologic symptoms ameliorated after steroid therapy. PMID:27458598

  7. Reduced-intensity conditioning allogeneic stem cell transplantation in malignant lymphoma: current status

    PubMed Central

    Zhang, Le; Zhang, Yi-Zhuo

    2013-01-01

    Allogeneic stem cell transplantation (allo-SCT) is a potential cure for patients with malignant lymphoma that is based on the graft-versus-lymphoma (GVL) effect. Myeloablative conditioning allo-SCT is associated with high mortality and morbidity, particularly in patients older than 45 years, heavily pretreated patients (prior hematopoietic stem cell transplantation or more than two lines of conventional chemotherapy) or patients affected by other comorbidities. Therefore, conventional allo-SCT is restricted to younger patients (<50 to 55 years) in good physical condition. Over the last decade, allo-SCT with reduced-intensity conditioning (RIC-allo-SCT) has been increasingly used to treat patients with lymphoma. This treatment is associated with lower toxicity and substantial decrease in the incidence of transplant-related mortality, and has the potential to lead to long-term remissions. Therefore, patients who are not suitable to undergo conventional allo-SCT can benefit from the potentially curative GVL effects of allo-SCT. Although RIC-allo-SCT has improved the survival of lymphoma patients, high post-transplant relapse rates or disease progression mainly results in treatment failure. Thus, further improvement is clearly needed. The role and timing of RIC-allo-SCT in the treatment of lymphoma remains unclear. Therefore, more prospective studies should clarify the effectiveness of this method. In this article, we review the recent literature on RIC-allo-SCT as a treatment for major lymphoma subtypes. Areas that require further investigation in the context of clinical trials are also highlighted. PMID:23691438

  8. Availability of Cord Blood Extends Allogeneic Hematopoietic Stem Cell Transplant Access to Racial and Ethnic Minorities

    PubMed Central

    Barker, Juliet N.; Byam, Courtney E.; Kernan, Nancy A.; Lee, Sinda S.; Hawke, Rebecca M.; Doshi, Kathleen A.; Wells, Deborah S.; Heller, Glenn; Papadopoulos, Esperanza B.; Scaradavou, Andromachi; Young, James W.; van den Brink., Marcel R. M.

    2013-01-01

    Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access due to the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ≥ 4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (p < 0.001). However, the majority of both groups had 5–6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (p < 0.001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (p < 0.001). Their median weight was significantly higher than CB transplant recipients (p < 0.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access. PMID:20800103

  9. Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation

    PubMed Central

    Inaba, Hiroto; Hartford, Christine M.; Pei, Deqing; Posner, Meredith J.; Yang, Jie; Hayden, Randall T.; Srinivasan, Ashok; Triplett, Brandon M.; McCulllers, Jon A.; Pui, Ching-Hon; Leung, Wing

    2011-01-01

    Summary The long-term antibody responses to re-immunization in recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been well studied. We prospectively and longitudinally evaluated the antibody responses to 8 vaccine antigens (diphtheria, tetanus, pertussis, measles, mumps, rubella, hepatitis B, and poliovirus) and assessed the factors associated with negative titres in 210 allo-HSCT recipients at St. Jude Children’s Research Hospital. Antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favourable, with either only transient antibody responses or persistently negative titres. Factors associated with vaccine failure were older age at immunization; lower CD3, CD4 or CD19 counts; higher IgM concentrations; positive recipient cytomegalovirus serology; negative titres before immunization; acute or chronic graft-versus-host disease; and radiation during preconditioning. These response patterns and clinical factors can be used to formulate re-immunization and monitoring strategies. Patients at risk for vaccine failure should have long-term follow-up; those with loss of antibody response or no seroconversion should receive booster immunizations. PMID:22017512

  10. Significance of Persistent Cytogenetic Abnormalities at Myeloablative Allogeneic Stem Cell Transplantation in First Complete Remission

    PubMed Central

    Oran, Betul; Popat, Uday; Rondon, Gabriella; Ravandi, Farhad; Garcia-Manero, Guillermo; Abruzzo, Lynn; Andersson, Borje S.; Bashir, Qaiser; Chen, Julianne; Kebriaei, Partow; Khouri, Issa F.; Koca, Ebru; Qazilbash, Muzaffar H.; Champlin, Richard; de Lima, Marcos

    2014-01-01

    Risk stratification is important to identify acute myeloid leukemia (AML) patients that might benefit from allogeneic hematopoietic stem cell transplantation (allo-HCT) in first complete remission (CR1). We retrospectively studied 150 AML patients with diagnostic cytogenetic abnormalities receiving myeloablative allo-HCT in CR1 to determine the prognostic impact of persistent cytogenetic abnormalities at allo-HCT. Three risk groups were identified: First group of patients with favorable/intermediate cytogenetics at diagnosis (n=49) and the second group with unfavorable cytogenetics at diagnosis but without the presence of persistent abnormal clone at allo-HCT (n=83) had similar 3-year leukemia free survival (LFS) of 58%-60% despite increased 3-year relapse incidence (RI) of 32.3% observed in the second risk group versus 16.8% in the first group. Third group of patients with unfavorable cytogenetics at diagnosis and persistence of that clone at allo-HCT (n=15) represented the worst prognostic group with 3-year RI of 57.5% and 3-year LFS of 29.2%. These data suggest that AML patients with unfavorable cytogenetics at diagnosis and persistence of abnormal clone at allo-HCT have high risk of relapse after allo-HCT. These patients should be considered for clinical trials designed to optimize conditioning regimens and/or to use preemptive strategies in the post-transplant setting to decrease the relapse incidence. PMID:22982533

  11. Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kawashima, Nozomu; Ito, Yoshinori; Sekiya, Yuko; Narita, Atsushi; Okuno, Yusuke; Muramatsu, Hideki; Irie, Masahiro; Hama, Asahito; Takahashi, Yoshiyuki; Kojima, Seiji

    2015-02-01

    Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

  12. Diffuse gastrointestinal bleeding and BK polyomavirus replication in a pediatric allogeneic haematopoietic stem cell transplant patient.

    PubMed

    Koskenvuo, M; Lautenschlager, I; Kardas, P; Auvinen, E; Mannonen, L; Huttunen, P; Taskinen, M; Vettenranta, K; Hirsch, H H

    2015-01-01

    Patients undergoing haematopoietic stem cell transplantation (HSCT) are at high risk of severe gastrointestinal bleeding caused by infections, graft versus host disease, and disturbances in haemostasis. BK polyomavirus (BKPyV) is known to cause hemorrhagic cystitis, but there is also evidence of BKV shedding in stool and its association with gastrointestinal disease. We report putative association of BKPyV replication with high plasma viral loads in a pediatric HSCT patient developing hemorrhagic cystitis and severe gastrointestinal bleeding necessitating intensive care. The observation was based on chart review and analysis of BKPyV DNA loads in plasma and urine as well as retrospective BKPyV-specific IgM and IgG measurements in weekly samples until three months post-transplant. The gastrointestinal bleeding was observed after a >100-fold increase in the plasma BKPyV loads and the start of hemorrhagic cystitis. The BKPyV-specific antibody response indicated past infection prior to transplantation, but increasing IgG titers were seen following BKPyV replication. The gastrointestinal biopsies were taken at a late stage of the episode and were no longer informative of BK polyomavirus involvement. In conclusion, gastrointestinal complications with bleeding are a significant problem after allogeneic HSCT to which viral infections including BKPyV may contribute. PMID:25542476

  13. Advances in conditioning regimens for older adults undergoing allogeneic stem cell transplantation to treat hematologic malignancies.

    PubMed

    William, Basem M; de Lima, Marcos

    2013-06-01

    Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for patients with hematological malignancies. These diseases, however, have their peak incidence in the sixth to eighth decades of life. Historically, elderly patients have been considered unsuitable candidates for SCT because of high treatment-related mortality (TRM). Over the past 15 years, the use of reduced-intensity conditioning (RIC) regimens before SCT has allowed patients in the sixth and seventh decades of life to be routinely transplanted. Despite major differences among transplant centers in the intensity and composition of the conditioning regimen and immunosuppression, choice of graft source, postgraft immunomodulation, and supportive care, there has been a dramatic decrease in TRM, allowing safer delivery of SCT. Major obstacles to SCT in elderly patients include donor availability, graft-versus-host disease, delayed immune recovery, multiple comorbidities, and chemo refractoriness. Here we review the current results of SCT in elderly patients, focusing on the role of RIC, and using myeloid diseases as the model for discussion.

  14. Balance function in patients who had undergone allogeneic hematopoietic stem cell transplantation.

    PubMed

    Morishita, Shinichiro; Kaida, Katsuji; Aoki, Osamu; Yamauchi, Shinya; Wakasugi, Tatsushi; Ikegame, Kazuhiro; Ogawa, Hiroyasu; Domen, Kazuhisa

    2015-09-01

    A previous study reported a 45% incidence of falling among allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients during hospitalisation. We investigated balance and physical function in allo-HSCT patients. Thirty patients (18 men and 12 women) who underwent allo-HSCT between February 2013 and September 2014 were included in this study. Patients were evaluated for up to 3 weeks before and 7 weeks after transplantation. Balance was evaluated using the Timed Up and Go test (TUG) and length of centre of pressure (CoP). Physical function was assessed using hand-grip strength, knee-extensor strength tests, and the 6 min walk test (6MWT). TUG and length of CoP were significantly increased following HSCT (P<0.01). Hand-grip strength, knee-extensor strength, and the 6MWT score decreased significantly after allo-HSCT (P<0.01). TUG and length of CoP were negatively correlated with hand grip and knee-extensor strength (P≤0.05). The allo-HSCT patients in this study had worsened dynamic and static movements of the CoP after transplantation as well as decline of physical function. Rehabilitation staff, nurses, and physicians should recognize the decreased balance function of patients who have undergone allo-HSCT.

  15. Digital PCR Panel for Sensitive Hematopoietic Chimerism Quantification after Allogeneic Stem Cell Transplantation.

    PubMed

    Stahl, Tanja; Rothe, Caroline; Böhme, Manja U; Kohl, Aloisa; Kröger, Nicolaus; Fehse, Boris

    2016-01-01

    Accurate and sensitive determination of hematopoietic chimerism is a crucial diagnostic measure after allogeneic stem cell transplantation to monitor engraftment and potentially residual disease. Short tandem repeat (STR) amplification, the current "gold standard" for chimerism assessment facilitates reliable accuracy, but is hampered by its limited sensitivity (≥1%). Digital PCR (dPCR) has been shown to combine exact quantification and high reproducibility over a very wide measurement range with excellent sensitivity (routinely ≤0.1%) and thus represents a promising alternative to STR analysis. We here aimed at developing a whole panel of digital-PCR based assays for routine diagnostic. To this end, we tested suitability of 52 deletion/insertion polymorphisms (DIPs) for duplex analysis in combination with either a reference gene or a Y-chromosome specific PCR. Twenty-nine DIPs with high power of discrimination and good performance were identified, optimized and technically validated. We tested the newly established assays on retrospective patient samples that were in parallel also measured by STR amplification and found excellent correlation. Finally, a screening plate for initial genotyping with DIP-specific duplex dPCR assays was designed for convenient assay selection. In conclusion, we have established a comprehensive dPCR system for precise and high-sensitivity measurement of hematopoietic chimerism, which should be highly useful for clinical routine diagnostics. PMID:27618030

  16. Relationship between HMGB1 and PAI-1 after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Nomura, Shosaku; Maeda, Yoshinobu; Ishii, Kazuyoshi; Katayama, Yuta; Yagi, Hideo; Fujishima, Naoto; Ota, Shuichi; Moriyama, Masato; Ikezoe, Takayuki; Miyazaki, Yasuhiko; Hayashi, Kunio; Fujita, Shinya; Satake, Atsushi; Ito, Tomoki; Kyo, Taiichi; Tanimoto, Mitsune

    2016-01-01

    Background Conditioning regimens including total body irradiation (TBI) or cyclophosphamide can mobilize high-mobility group box 1 (HMGB1) to peripheral blood. Additionally, increased plasminogen activator inhibitor (PAI)-1 levels are associated with post-allogeneic hematopoietic stem cell transplantation (aHSCT). However, changes to circulating levels of HMGB1 after aHSCT are poorly understood. Materials and methods The study cohort included 289 patients who underwent aHSCT at one of 25 institutions in Japan. We have investigated the relationship between HMGB1 and PAI-1 following aHSCT. A significant increase in HMGB1 levels occurred after conditioning treatment. Additionally, levels of HMGB1 at day 0 were significantly increased in TBI+ patients and cyclophosphamide/TBI patients. Conclusion Our data revealed that an increased level of HMGB1 at day 0 following aHSCT correlates with increased PAI-1 after aHSCT, which is consistent with previous reports. Increased HMGB1 at day 0 after a conditioning regimen may play a role in transplantation-associated coagulopathy following aHSCT, because PAI-1 can accelerate procoagulant activity. PMID:26848281

  17. Digital PCR Panel for Sensitive Hematopoietic Chimerism Quantification after Allogeneic Stem Cell Transplantation

    PubMed Central

    Stahl, Tanja; Rothe, Caroline; Böhme, Manja U.; Kohl, Aloisa; Kröger, Nicolaus; Fehse, Boris

    2016-01-01

    Accurate and sensitive determination of hematopoietic chimerism is a crucial diagnostic measure after allogeneic stem cell transplantation to monitor engraftment and potentially residual disease. Short tandem repeat (STR) amplification, the current “gold standard” for chimerism assessment facilitates reliable accuracy, but is hampered by its limited sensitivity (≥1%). Digital PCR (dPCR) has been shown to combine exact quantification and high reproducibility over a very wide measurement range with excellent sensitivity (routinely ≤0.1%) and thus represents a promising alternative to STR analysis. We here aimed at developing a whole panel of digital-PCR based assays for routine diagnostic. To this end, we tested suitability of 52 deletion/insertion polymorphisms (DIPs) for duplex analysis in combination with either a reference gene or a Y-chromosome specific PCR. Twenty-nine DIPs with high power of discrimination and good performance were identified, optimized and technically validated. We tested the newly established assays on retrospective patient samples that were in parallel also measured by STR amplification and found excellent correlation. Finally, a screening plate for initial genotyping with DIP-specific duplex dPCR assays was designed for convenient assay selection. In conclusion, we have established a comprehensive dPCR system for precise and high-sensitivity measurement of hematopoietic chimerism, which should be highly useful for clinical routine diagnostics. PMID:27618030

  18. Digital PCR Panel for Sensitive Hematopoietic Chimerism Quantification after Allogeneic Stem Cell Transplantation.

    PubMed

    Stahl, Tanja; Rothe, Caroline; Böhme, Manja U; Kohl, Aloisa; Kröger, Nicolaus; Fehse, Boris

    2016-01-01

    Accurate and sensitive determination of hematopoietic chimerism is a crucial diagnostic measure after allogeneic stem cell transplantation to monitor engraftment and potentially residual disease. Short tandem repeat (STR) amplification, the current "gold standard" for chimerism assessment facilitates reliable accuracy, but is hampered by its limited sensitivity (≥1%). Digital PCR (dPCR) has been shown to combine exact quantification and high reproducibility over a very wide measurement range with excellent sensitivity (routinely ≤0.1%) and thus represents a promising alternative to STR analysis. We here aimed at developing a whole panel of digital-PCR based assays for routine diagnostic. To this end, we tested suitability of 52 deletion/insertion polymorphisms (DIPs) for duplex analysis in combination with either a reference gene or a Y-chromosome specific PCR. Twenty-nine DIPs with high power of discrimination and good performance were identified, optimized and technically validated. We tested the newly established assays on retrospective patient samples that were in parallel also measured by STR amplification and found excellent correlation. Finally, a screening plate for initial genotyping with DIP-specific duplex dPCR assays was designed for convenient assay selection. In conclusion, we have established a comprehensive dPCR system for precise and high-sensitivity measurement of hematopoietic chimerism, which should be highly useful for clinical routine diagnostics.

  19. Minimal residual disease monitoring and preemptive immunotherapy in myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mo, Xiao-Dong; Qin, Ya-Zhen; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2016-08-01

    This study investigated the efficacy of minimal residual disease (MRD) monitoring and MRD-directed preemptive immunotherapy in high-risk myelodysplastic syndrome (MDS) patients who received allogeneic hematopoietic stem cell transplantation (HSCT). MRD assessment consisted of Wilms' tumor gene 1 (WT1) detection with PCR and leukemia-associated immunophenotypic pattern examination with multiparameter flow cytometry (FCM). Post-HSCT, 31 patients were positive for WT1, and 8, for FCM; positivity for WT1 (18.6 vs. 6.1 %, P = 0.040) or FCM (62.5 vs. 3.6 %, P < 0.001) indicated a higher 2-year relapse rate. Twenty-one patients met our combined criteria for MRD, and the presence of MRD was associated with a higher 2-year relapse rate (27.3 vs. 4.5 %, P = 0.003). Preferentially expressed antigen of melanoma (PRAME) expression alone was not an appropriate MRD marker; however, it suggested that the MRD-positive patients may fail to respond to preemptive immunotherapy. In patients positive for both PRAME and MRD, the relapse rate was 60 % despite preemptive immunotherapy. Multivariate analysis confirmed the association between the increased relapse rate and positivity for both PRAME and MRD (hazard ratio = 42.8, P = 0.001). MRD monitoring predicted relapse in high-risk MDS post-HSCT patients, and PRAME- and MRD-positive patients did not benefit from preemptive immunotherapy.

  20. BK viremia precedes hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation.

    PubMed

    Laskin, Benjamin L; Denburg, Michelle; Furth, Susan; Diorio, Donna; Goebel, Jens; Davies, Stella M; Jodele, Sonata

    2013-08-01

    BK virus is associated with hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT), although evidence supporting a causal relationship remains limited. Although BK viruria is common after HSCT, BK viremia may better predict clinically significant cystitis, similar to its predictive value for nephropathy after kidney transplantation. We hypothesized that BK viremia would precede hemorrhagic cystitis in a cohort of 88 consecutive children prospectively enrolled to originally study thrombotic microangiopathy in the first 100 days after allogeneic HSCT. Cox regression models with time-varying covariates assessed the association between different BK viremia cutoffs and the development of hemorrhagic cystitis, defined as at least macroscopic hematuria. Subjects with a peak plasma BK viral load 1 to 9999 copies/mL had an adjusted hazard ratio of 4.2 (95% confidence interval (CI), 1.3 to 13.7) for the development of hemorrhagic cystitis. Those with peak BK viremia >100,000 copies/mL had an adjusted hazard ratio of 116.8 (95% CI, 12 to 1136) for cystitis. Other independent risk factors for hemorrhagic cystitis included age >7 years and HHV-6 viremia. Neither graft-versus-host disease nor achieving engraftment increased the risk for cystitis. If therapeutic strategies are found to be effective, these observations may support screening for BK viremia after HSCT, as currently recommended for other DNA viruses.

  1. Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome.

    PubMed

    Shiratori, Souichi; Fujimoto, Katsuya; Nishimura, Machiko; Hatanaka, Kanako C; Kosugi-Kanaya, Mizuha; Okada, Kohei; Sugita, Junichi; Shigematsu, Akio; Hashimoto, Daigo; Endo, Tomoyuki; Kondo, Takeshi; Abe, Riichiro; Hashino, Satoshi; Matsuno, Yoshihiro; Shimizu, Hiroshi; Teshima, Takanori

    2016-03-01

    Advanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954 days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and 'down-staging' effect from advanced stage to early stage by HSCT improve the prognosis of advanced-stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS.

  2. Biopsy-verified bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Uhlving, Hilde Hylland; Andersen, Claus B; Christensen, Ib Jarle; Gormsen, Magdalena; Pedersen, Karen Damgaard; Buchvald, Frederik; Heilmann, Carsten; Nielsen, Kim Gjerum; Mortensen, Jann; Moser, Claus; Sengeløv, Henrik; Müller, Klaus Gottlob

    2015-03-01

    Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases. PMID:25498923

  3. Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Vantyghem, Marie-Christine; Cornillon, Jérôme; Decanter, Christine; Defrance, Frédérique; Karrouz, Wassila; Leroy, Clara; Le Mapihan, Kristell; Couturier, Marie-Anne; De Berranger, Eva; Hermet, Eric; Maillard, Natacha; Marcais, Ambroise; Francois, Sylvie; Tabrizi, Reza; Yakoub-Agha, Ibrahim

    2014-10-29

    Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

  4. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo

    SciTech Connect

    Lee, Miyoung; Jeong, Sang Young; Ha, Jueun; Kim, Miyeon; Jin, Hye Jin; Kwon, Soon-Jae; Chang, Jong Wook; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Kim, Jae-Sung; Jeon, Hong Bae

    2014-04-18

    Highlights: • hUCB-MSCs maintained low immunogenicity even after immune challenge in vitro. • Humanized NSG mice were established using human UCB CD34+ cells. • Repeated intravenous hUCB-MSC injection into mice did not lead to immune responses and adverse events. • Allogeneic hUCB-MSCs maintained low immunogenicity in vitro and in vivo. - Abstract: Evaluation of the immunogenicity of human mesenchymal stem cells (MSCs) in an allogeneic setting during therapy has been hampered by lack of suitable models due to technical and ethical limitations. Here, we show that allogeneic human umbilical cord blood derived-MSCs (hUCB-MSCs) maintained low immunogenicity even after immune challenge in vitro. To confirm these properties in vivo, a humanized mouse model was established by injecting isolated hUCB-derived CD34+ cells intravenously into immunocompromised NOD/SCID IL2γnull (NSG) mice. After repeated intravenous injection of human peripheral blood mononuclear cells (hPBMCs) or MRC5 cells into these mice, immunological alterations including T cell proliferation and increased IFN-γ, TNF-α, and human IgG levels, were observed. In contrast, hUCB-MSC injection did not elicit these responses. While lymphocyte infiltration in the lung and small intestine and reduced survival rates were observed after hPBMC or MRC5 transplantation, no adverse events were observed following hUCB-MSC introduction. In conclusion, our data suggest that allogeneic hUCB-MSCs have low immunogenicity in vitro and in vivo, and are therefore “immunologically safe” for use in allogeneic clinical applications.

  5. Acupoint Injection of Autologous Stromal Vascular Fraction and Allogeneic Adipose-Derived Stem Cells to Treat Hip Dysplasia in Dogs

    PubMed Central

    Marx, Camila; Silveira, Maiele Dornelles; Selbach, Isabel; da Silva, Ariel Silveira; Braga, Luisa Maria Gomes de Macedo; Camassola, Melissa; Nardi, Nance Beyer

    2014-01-01

    Stem cells isolated from adipose tissue show great therapeutic potential in veterinary medicine, but some points such as the use of fresh or cultured cells and route of administration need better knowledge. This study aimed to evaluate the effect of autologous stromal vascular fraction (SVF, n = 4) or allogeneic cultured adipose-derived stem cells (ASCs, n = 5) injected into acupuncture points in dogs with hip dysplasia and weak response to drug therapy. Canine ASCs have proliferation and differentiation potential similar to ASCs from other species. After the first week of treatment, clinical evaluation showed marked improvement compared with baseline results in all patients treated with autologous SVF and three of the dogs treated with allogeneic ASCs. On days 15 and 30, all dogs showed improvement in range of motion, lameness at trot, and pain on manipulation of the joints, except for one ASC-treated patient. Positive results were more clearly seen in the SVF-treated group. These results show that autologous SVF or allogeneic ASCs can be safely used in acupoint injection for treating hip dysplasia in dogs and represent an important therapeutic alternative for this type of pathology. Further studies are necessary to assess a possible advantage of SVF cells in treating joint diseases. PMID:25180040

  6. Comparison of autogenic and allogenic bone marrow derived mesenchymal stem cells for repair of segmental bone defects in rabbits.

    PubMed

    Udehiya, Rahul Kumar; Amarpal; Aithal, H P; Kinjavdekar, P; Pawde, A M; Singh, Rajendra; Taru Sharma, G

    2013-06-01

    Autogenic and allogenic bone marrow derived mesenchymal stem cells (BM-MSCs) were compared for repair of bone gap defect in rabbits. BM-MSCs were isolated from bone marrow aspirates and cultured in vitro for allogenic and autogenic transplantation. A 5mm segmental defect was created in mid-diaphysis of the radius bone. The defect was filled with hydroxyapatite alone, hydroxyapatite with autogeneic BM-MSCs and hydroxyapatite with allogenic BM-MSCs in groups A, B and C, respectively. On an average 3.45×10(6) cells were implanted at each defect site. Complete bridging of bone gap with newly formed bone was faster in both treatment groups as compared to control group. Histologically, increased osteogenesis, early and better reorganization of cancellous bone and more bone marrow formation were discernible in treatment groups as compared to control group. It was concluded that in vitro culture expanded allogenic and autogenic BM-MSCs induce similar, but faster and better healing as compared to control.

  7. Specially modified stromal and immune microenvironment in injected bone marrow following intrabone transplantation facilitates allogeneic hematopoietic stem cell engraftment.

    PubMed

    Chen, Chen; Su, Yingjun; Chen, Jianwu; Song, Yajuan; Zhuang, Ran; Xiao, Bo; Guo, Shuzhong

    2016-07-01

    For allogeneic hematopoietic stem cell transplantation (HSCT), the first key step is the engraftment of hematopoietic stem cells (HSCs) across the major histocompatibility complex (MHC) barrier. Intrabone bone marrow transplantation (IBBMT) could replace more recipient stromal cells with donor cells and facilitate allogeneic organ transplantation compared with the conventional intravenous approach. However, it remains unknown whether and how IBBMT reconstructs the immune microenvironment for allogeneic HSCs. We explored where the BM microenvironment changes by determining BM stromal cell chimerism and measuring the change in CXCL-12 expression and regulatory T cells in recipient BM. We found that most stromal cells were replaced by allogeneic cells in the injected BM, with higher expression of immune regulatory cytokines (interleukin-10) compared with the contralateral BM and the intravenous group BM. This difference was independent of injury caused by intrabone injection. Consistent with the microenvironment modification, the allogeneic the engraftment rate and reconstitution capacity of HSCs were enhanced in the injected BM compared with the contralateral BM and intravenous group BM. Surgical removal of the injected bone at 7 days rather than 21 days reduced the levels of allogeneic granulocytes and HSCs in the peripheral blood. In conclusion, IBBMT specially modifies stromal cells in the injected BM which provide immune protective cues that improve the engraftment of allogeneic HSCs in an early period. PMID:27090963

  8. Patients' perception of health-related quality of life during the first year after autologous and allogeneic stem cell transplantation.

    PubMed

    Andersson, I; Ahlberg, K; Stockelberg, D; Persson, L-O

    2011-05-01

    Little attention has been paid to examine health-related quality of life (HRQoL) the first year post-transplant, despite that this period is crucial for returning to normal life and functioning and to prevent delayed psychosocial adjustment. The purpose of the present study was to describe HRQoL after autologous versus allogeneic stem cell transplantations during the first year post-transplant. The allogeneic group was further divided into two groups: allogeneic stem cell transplantation after reduced intensive conditioning and allogeneic stem cell transplantation after myeloablative conditioning. All together 202 patients were enrolled in the study. HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the treatment-specific module High-Dose Chemotherapy (HDC-19). The questionnaires were filled out at six occasions (from inclusion to 12 months after transplantation). The reduced intensive conditioning group seemed to recover in the same way as the autologous group and these two groups were closer in their scoring compared with the myeloablative conditioning group. One month after the transplantation there were no significant differences in change scores between the autologous and reduced intensive conditioning group, and 1 year after the transplantation levels of symptoms and functioning were back to baseline or better. The myeloablative conditioning group, who perceived more symptoms and lower levels of functioning during the whole period, was still impaired in 10 out of 29 scales 1 year after the transplantation and no significant improvements compared with baseline were observed for this group.

  9. Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Wunderli, Werner; Meerbach, Astrid; Güngör, Tayfun; Guengoer, Tayfun; Berger, Christoph; Greiner, Oliver; Caduff, Rosmarie; Trkola, Alexandra; Bossart, Walter; Gerlach, Daniel; Schibler, Manuel; Cordey, Samuel; McKee, Thomas Alexander; Van Belle, Sandra; Kaiser, Laurent; Tapparel, Caroline

    2011-01-01

    Infants with severe primary combined immunodeficiency (SCID) and children post-allogeneic hematopoietic stem cell transplantation (HSCT) are extremely susceptible to unusual infections. The lack of generic tools to detect disease-causing viruses among more than 200 potential human viral pathogens represents a major challenge to clinicians and virologists. We investigated retrospectively the causes of a fatal disseminated viral infection with meningoencephalitis in an infant with gamma C-SCID and of chronic gastroenteritis in 2 other infants admitted for HSCT during the same time period. Analysis was undertaken by combining cell culture, electron microscopy and sequence-independent single primer amplification (SISPA) techniques. Caco-2 cells inoculated with fecal samples developed a cytopathic effect and non-enveloped viral particles in infected cells were detected by electron microscopy. SISPA led to the identification of astrovirus as the pathogen. Both sequencing of the capsid gene and the pattern of infection suggested nosocomial transmission from a chronically excreting index case to 2 other patients leading to fatal infection in 1 and to transient disease in the others. Virus-specific, real-time reverse transcription polymerase chain reaction was then performed on different stored samples to assess the extent of infection. Infection was associated with viremia in 2 cases and contributed to death in 1. At autopsy, viral RNA was detected in the brain and different other organs, while immunochemistry confirmed infection of gastrointestinal tissues. This report illustrates the usefulness of the combined use of classical virology procedures and modern molecular tools for the diagnosis of unexpected infections. It illustrates that astrovirus has the potential to cause severe disseminated lethal infection in highly immunocompromised pediatric patients. PMID:22096580

  10. Fetal Liver-Derived Mesenchymal Stem Cell Engraftment After Allogeneic In Utero Transplantation into Rabbits

    PubMed Central

    Moreno, Rafael; Martínez-González, Itziar; Rosal, Marta; Nadal, Marga; Petriz, Jordi; Gratacós, Eduard

    2012-01-01

    Prenatal transplantation of genetically engineered mesenchymal stem cells (MSCs) might benefit prevention or treatment of early-onset genetic disorders due to the cells' intrinsic regenerative potential plus the acquired advantage from therapeutic transgene expression. However, a thorough assessment of the safety, accessibility, and behavior of these MSCs in the fetal environment using appropriate animal models is required before we can advance toward a clinical application. We have recently shown that fetal rabbit liver MSCs (fl-MSCs) have superior growth rate, clonogenic capability, and in vitro adherence and differentiation abilities compared with adult rabbit bone marrow MSCs. In this follow-up study, we report safe and widespread distribution of recombinant pSF-EGFP retrovirus-transduced fl-MSCs (EGFP+-fl-MSCs) in neonatal rabbit tissues at 10 days after fetal allogeneic transplantation through both intrahepatic and intra-amniotic administration. Conversely, a more restricted biodistribution pattern according to the route of administration was apparent in the young rabbits intervened at 16 weeks after fetal EGFP+-fl-MSC transplantation. Furthermore, the presence of these cells in the recipients' tissues, tracked with the reporter provirus, was inversely related to the developmental stage of the fetuses at the time of intervention. Long-term engraftment was confirmed both by fluorescence in situ hybridization analysis on touch tissue imprints using a chromosome Y-specific BAC probe, and by immunohistochemical localization of EGFP expression. Finally, there was no evidence of immune responses against the transplanted EGFP+-fl-MSCs or the EGFP transgenic product in the treated young rabbits. Thus, cell transplantation approaches using genetically engineered fetal MSCs may prove particularly valuable to frontier medical treatments for congenital birth defects in perinatology. PMID:21495909

  11. Ex Vivo Expanded Allogeneic Mesenchymal Stem Cells With Bone Marrow Transplantation Improved Osteogenesis in Infants With Severe Hypophosphatasia.

    PubMed

    Taketani, Takeshi; Oyama, Chigusa; Mihara, Aya; Tanabe, Yuka; Abe, Mariko; Hirade, Tomohiro; Yamamoto, Satoshi; Bo, Ryosuke; Kanai, Rie; Tadenuma, Taku; Michibata, Yuko; Yamamoto, Soichiro; Hattori, Miho; Katsube, Yoshihiro; Ohnishi, Hiroe; Sasao, Mari; Oda, Yasuaki; Hattori, Koji; Yuba, Shunsuke; Ohgushi, Hajime; Yamaguchi, Seiji

    2015-01-01

    Patients with severe hypophosphatasia (HPP) develop osteogenic impairment with extremely low alkaline phosphatase (ALP) activity, resulting in a fatal course during infancy. Mesenchymal stem cells (MSCs) differentiate into various mesenchymal lineages, including bone and cartilage. The efficacy of allogeneic hematopoietic stem cell transplantation for congenital skeletal and storage disorders is limited, and therefore we focused on MSCs for the treatment of HPP. To determine the effect of MSCs on osteogenesis, we performed multiple infusions of ex vivo expanded allogeneic MSCs for two patients with severe HPP who had undergone bone marrow transplantation (BMT) from asymptomatic relatives harboring the heterozygous mutation. There were improvements in not only bone mineralization but also muscle mass, respiratory function, and mental development, resulting in the patients being alive at the age of 3. After the infusion of MSCs, chimerism analysis of the mesenchymal cell fraction isolated from bone marrow in the patients demonstrated that donor-derived DNA sequences existed. Adverse events of BMT were tolerated, whereas those of MSC infusion did not occur. However, restoration of ALP activity was limited, and normal bony architecture could not be achieved. Our data suggest that multiple MSC infusions, following BMT, were effective and brought about clinical benefits for patients with lethal HPP. Allogeneic MSC-based therapy would be useful for patients with other congenital bone diseases and tissue disorders if the curative strategy to restore clinically normal features, including bony architecture, can be established.

  12. Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders

    PubMed Central

    Mahmoud, Hossam K.; Elhaddad, Alaa M.; Fahmy, Omar A.; Samra, Mohamed A.; Abdelfattah, Raafat M.; El-Nahass, Yasser H.; Fathy, Gamal M.; Abdelhady, Mohamed S.

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a geno-identical matched sibling (MSD) is one of the most successful therapies in patients with non-malignant hematological disorders. This study included 273 patients with severe aplastic anemia (SAA), 152 patients with B-Thalassemia major (BTM), 31 patients with Fanconi’s anemia (FA), 20 patients with congenital immunodeficiency diseases (ID), and 13 patients with inherited metabolic disorders (IMD) allografted from a MSD. In SAA, the 8-year overall survival (OS) of the whole group patients was 74%. OS was significantly better in patients conditioned with fludarabine and cyclophosphamide (Flu/Cy) than in those who received cyclophosphamide and antithymocyte globulin (Cy/ATG) (p = 0.021). Acute graft-versus-host disease (aGVHD) grade II–IV occurred in 15% while chronic GVHD (cGVHD) occurred in 28%. In BTM, the 12-year disease-free survival (DFS) of the whole group of BTM patients was 72.4%. DFS was 74% for peripheral blood stem cell (PBSC) group compared to 64% in the BM stem cell group. The incidence of graft rejection was significantly lower in patients who received PBSC than in those who received BM (9% vs 25%) (p = 0.036). AGVHD grade II–IV and cGVHD occurred in 15% and 12% of the whole group of BTM patients respectively. In FA, the 5-year OS was 64.5%. Graft rejection occurred in 10% of patients. Grade II–IV aGVHD occurred in 16% while cGVHD occurred in 4%. In ID, the 5-year OS was 62%. Graft rejection occurred in two (10%) patients. Three patients (15%) developed grade II–IV aGVHD, 2 of them progressed to secondary cGVHD. In IMD, OS was 46% at 5 years. Graft rejection occurred in 8% of patients. AGVHD grade II–IV occurred in 15% while cGVHD occurred in 14%. In conclusion, Allo-HSCT provides a higher DFS rate over conventional therapies for patients with non-malignant hematological disorders with prolonged survival. PMID:26257943

  13. Post-allogeneic Hematopoietic Stem Cell Transplantation (HSCT) changes in inorganic salivary components.

    PubMed

    Boer, C C; Correa, M E P; Tenuta, L M A; Souza, C A; Vigorito, A C

    2015-09-01

    Recent studies have considered the qualitative and quantitative assessment of salivary flow, as well the biochemical components of saliva, as possible biomarkers that might contribute to the pathogenesis of chronic graft-versus-host disease (cGHVD) in hematopoietic stem cell transplantation (HSCT) patients. The aim of this study was to evaluate prospectively the inorganic salivary status at different periods of allogeneic HSCT. Saliva collection and oral examination were performed prior to the HSCT, ​between days 8 and 10, days 80 and 100, and at the cGVHD onset. Concentrations of calcium (Ca), phosphate (Pi), chloride (Cl), magnesium (Mg), potassium (K), and sodium (Na) were performed using colorimetric reactions and atomic absorption. Fifty-five consecutive patients undergoing first allogeneic HSCT were included in this study. Between days 8 and 10, the salivary flow rate was significantly higher (p = 0.05), Pi concentration was decreased (p = 0.007), and Na and Cl were increased (p = 0.001 and p = 0.001, respectively), compared with the baseline. Salivary flow rate during the same period showed a negative correlation with Pi concentration (p = 0.02) and a positive correlation with Na and Cl concentrations (p = 0.003 and p = 0.001, respectively). The salivary flow rate was decreased between days 80 and 100 (p = 0.02) and Na, Cl, and K concentrations were increased (p = 0.03, p = 0.02, and p = 0.003, respectively). Salivary flow rate showed a negative correlation with Na and Cl (p = 0.01 and p = 0.013, respectively). At cGVHD onset, the salivary flow rate showed no statistical difference compared with the other studied periods. A trend was observed in the higher Na concentration compared with the baseline (p = 0.06) and Pi concentration presented a significant decrease (p = 0.004). Ca and Mg concentrations showed no changes during all evaluation periods. The present study showed changes in inorganic

  14. Weight Loss and Decrease of Body Mass Index during Allogeneic Stem Cell Transplantation Are Common Events with Limited Clinical Impact

    PubMed Central

    Rieger, Christina T.; Wischumerski, Isabel; Rust, Christian; Fiegl, Michael

    2015-01-01

    Purpose Weight loss in cancer patients has been attributed with significant morbidity and mortality. During allogeneic stem cell transplantation (SCT), oral nutrition is often hampered and hence total parenteral nutrition (TPN) is necessary. We therefore investigated the course of weight during stem cell transplantation and the clinical consequences of weight change. Methods 180 consecutive patients who received allogeneic SCT between January 2010 and December 2011 at our center were analyzed for weight loss, laboratory and clinical parameters. Results During SCT, a median decrease of 6.6% of body mass index (BMI) was observed for the whole population (from 25.3 at admission to 23.6 at discharge), and a 1.6fold increase of malnutrition despite use of TPN (28.3% to 45.0%). 55.6% of patients experienced a significant weight loss of ≥5% with a median decrease of 9.2% in BMI. Serum levels of albumin, total protein and cholesterol rapidly decreased during conditioning therapy. After a median of 2.4 years, the median BMI was still only 23.4 (not different from discharge). However, we did not observe a meaningful difference in side effects and survival between patients that did or did not lose weight. Conclusion Weight loss is commonly observed during allogeneic SCT despite TPN, but the clinical consequences thereof seem limited: we observed no significant impact on patients with a decrease ≥ 5% in BMI on transplant outcome, side effects or survival. PMID:26683031

  15. Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial.

    PubMed

    Lee, Dean A; Denman, Cecele J; Rondon, Gabriela; Woodworth, Glenda; Chen, Julianne; Fisher, Tobi; Kaur, Indreshpal; Fernandez-Vina, Marcelo; Cao, Kai; Ciurea, Stefan; Shpall, Elizabeth J; Champlin, Richard E

    2016-07-01

    Allogeneic stem cell transplantation is an effective treatment for high-risk myeloid malignancies, but relapse remains the major post-transplantation cause of treatment failure. Alloreactive natural killer (NK) cells mediate a potent antileukemic effect and may also enhance engraftment and reduce graft-versus-host disease (GVHD). Haploidentical transplantations provide a setting in which NK cell alloreactivity can be manipulated, but they are associated with high rates of GVHD. We performed a phase I study infusing escalating doses of NK cells from an HLA haploidentical-related donor-selected for alloreactivity when possible-as a component of the preparative regimen for allotransplantation from a separate HLA-identical donor. The goal of infusing third-party alloreactive NK cells was to augment the antileukemic effect of the transplantation without worsening GVHD and, thus, improve the overall outcome of hematopoietic transplantation. Twenty-one patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia refractory or beyond first remission received a preparative regimen with busulfan and fludarabine followed by infusion of apheresis-derived, antibody-selected, and IL-2-activated NK cells. Doses were initially based on total nucleated cell (TNC) content and later based on CD56(+) cells to reduce variability. CD56(+) content ranged from .02 to 8.32 × 10(6)/kg. IL-2, .5 × 10(6) units/m(2) subcutaneously was administered daily for 5 days in the final cohort (n = 10). CD3(+) cells in the NK cell product were required to be < 10(5)/kg. Median relapse-free, overall, and GVHD-free/relapse-free survival for all patients enrolled was 102, 233, and 89 days, respectively. Five patients are alive, 5 patients died of transplantation-related causes, and 11 patients died of relapse. Despite the small sample size, survival was highly associated with CD56(+) cells delivered (P = .022) and development of

  16. Romidepsin used as monotherapy in sequence with allogeneic stem cell transplant in a patient with peripheral T-cell lymphoma.

    PubMed

    Finn, Nicholas; Larouche, Jean-Francois

    2014-01-01

    Despite advances in the field, a clear treatment algorithm for most peripheral T-cell lymphoma (PTCL) subtypes remains to be defined. Generating reliable randomized data for this type of pathology remains a challenge because of the relative rarity of the disease and the heterogeneity of subtypes. Newer agents, such as the class-I selective histone deacetylase inhibitor romidepsin, have demonstrated efficacy and manageable toxicity in the relapsed and refractory setting. Whether novel agents should be used in conjunction with more conventional cytotoxic therapies or in sequence with a transplant strategy is unknown at this time. Here we report the successful use of romidepsin monotherapy as a bridge to allogeneic stem cell transplantation in a patient who had previously relapsed after several lines of conventional cytotoxic therapy for PTCL. Romidepsin provided the patient with sufficient disease control to proceed to transplantation while remaining in complete remission.

  17. BK virus disease after allogeneic stem cell transplantation: a cohort analysis.

    PubMed

    Rorije, Nienke M G; Shea, Margaret M; Satyanarayana, Gowri; Hammond, Sarah P; Ho, Vincent T; Baden, Lindsey R; Antin, Joseph H; Soiffer, Robert J; Marty, Francisco M

    2014-04-01

    The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.

  18. Clinicopathological analysis of allogeneic hematopoietic stem cell transplantation-related membranous glomerulonephritis.

    PubMed

    Hiramatsu, Rikako; Ubara, Yoshifumi; Sawa, Naoki; Hasegawa, Eiko; Kawada, Masahiro; Imafuku, Aya; Sumida, Keiichi; Mise, Koki; Yamanouchi, Masayuki; Ueno, Toshiharu; Sekine, Akinari; Hayami, Noriko; Suwabe, Tatsuya; Hoshino, Junichi; Takaichi, Kenmei; Ohashi, Kenichi; Fujii, Takeshi; Wake, Atsushi; Taniguchi, Shuichi

    2016-04-01

    Allogeneic hematopoietic stem cell transplantation (HSCT)-related membranous glomerulonephritis (MGN) is poorly understood. A total of 830 patients who underwent HSCT at Toranomon Hospital from 2000 to 2012 were evaluated retrospectively, including 621 patients receiving umbilical cord blood transplantation (UCBT) and 208 patients receiving unrelated bone marrow transplantation. MGN was diagnosed in 5 patients after UCBT (versus none after bone marrow transplantation) and occurred concomitantly with chronic graft-versus-host disease after cessation of immunosuppression. Light microscopy did not show any definite spikes or bubbling of the glomerular basement membrane (GBM) in all 5 patients. In 1 patient (case 5), endocapillary proliferative lesions with fibrin-like deposits were noted in addition to MGN findings. Immunofluorescence demonstrated granular deposits of immunoglobulin G (IgG; IgG1 and IgG4) along the GBM with negativity for C3, C4, and C1q in 4 patients (cases 1-4), whereas case 5 showed positivity for IgG (IgG1, IgG2, IgG3, and IgG4) as well as for C3, C4, and C1q. Electron microscopy revealed electron-dense deposits in the subepithelial space of the GBM in cases 1-4. In case 5, electron-dense deposits were present in the mesangium and the subendothelial space of the GBM, as well as in the subepithelial space. After treatment with immunosuppressants (prednisolone and/or cyclosporin) or angiotensin-converting enzyme inhibitors, complete remission with disappearance of proteinuria was achieved 12.2 months in all 5 patients, but nephrotic-range proteinuria relapsed in 2 patients during follow-up. Serum anti-PLA2R autoantibody was negative in 3 patients. HSCT-related MGN only occurred after UCBT. We believe that there were 2 morphologic patterns: early MGN and membranoproliferative pattern glomerulonephritis.

  19. Allogeneic stem cell transplantation in hematological disorders: single center experience from Pakistan.

    PubMed

    Ullah, K; Ahmed, P; Raza, S; Satti, T; Nisa, Q; Mirza, S; Akhtar, F; Kamal, M K; Akhtar, F M

    2007-12-01

    One hundred and fifty-four patients received allogeneic stem cell transplantations from HLA-matched siblings for various hematological disorders from July 2001 to September 2006. Indications for transplantation included aplastic anemia (n=66), beta-thalassemia major (n=40), CML (n=33), acute leukemia (n=8), and miscellaneous disorders (n=7). One hundred and twenty patients were males and 34 were females. Median patient age was 14 years (range, 1(1/4)-54 years). All patients achieved successful engraftment. Median time to engraftment (ANC>0.5x10(9)/L) was 14 days. Posttransplant complications encountered in our patients included acute graft versus host disease (GvHD) (grade II-IV) 28.5%, chronic GvHD 15.5%, hemorrhagic cystitis 9.7%, VOD liver 5.1%, acute renal failure 3.2%, bacterial infections 51.2%, fungal infections 15.0%, cytomegalovirus (CMV) infection 4%, herpes zoster 4%, tuberculosis 2.6%, Pneumocystis jirovicii infection 0.6%, malaria 0.6% patients, graft rejection 5.2% patients, and relapse in 4% patients. Certain unexpected and rare posttransplant complications were also observed in our patients. These included Hickman catheter embolization, Guillain-Barré (GB) syndrome, deep vein thrombosis, hemorrhagic pericarditis with clots leading to cardiac tamponade, idiopathic polycythemia, dengue fever, and cyclosporine-induced neurotoxicity. Mortality was observed in 27.2% patients. Major causes of mortality were GvHD, VOD, disease relapse, intracranial hemorrhage, acute renal failure, pseudomonas septicemia, tuberculosis, disseminated aspergillosis, and CMV infection. At 5 years, overall survival (OS) and disease-free survival (DFS) rates were 72.5% and 70.7%, respectively.

  20. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

    PubMed Central

    Alho, Ana C.; Kim, Haesook T.; Chammas, Marie J.; Reynolds, Carol G.; Matos, Tiago R.; Forcade, Edouard; Whangbo, Jennifer; Nikiforow, Sarah; Cutler, Corey S.; Koreth, John; Ho, Vincent T.; Armand, Philippe; Antin, Joseph H.; Alyea, Edwin P.; Lacerda, Joao F.; Soiffer, Robert J.

    2016-01-01

    The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. PMID:26670634

  1. Superselective arterial embolization of the superior mesenteric artery for the treatment of gastrointestinal hemorrhage following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Chen, Run-Zhe; Zhao, Gang; Jin, Nan; Chen, Bao-An; Ding, Jia-Hua

    2014-01-01

    Superselective arterial embolization is a common therapeutic procedure for cases of visceral hemorrhage. However, until now, it has not been applied in the treatment of gastrointestinal (GI) hemorrhage caused by acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. We describe a case presenting with persistent GI bleeding associated with acute GVHD successfully treated by superselective arterial embolization of the superior mesenteric artery with gelatin sponge after noneffective conventional management. This case will help guide hematologists to deal with a similar situation in the future. PMID:25419120

  2. Successful treatment of small cell variant anaplastic large cell lymphoma with allogeneic peripheral blood stem cell transplantation, and review of the literature.

    PubMed

    Imamura, Rie; Mouri, Fumihiko; Nomura, Kei; Nakamura, Takayuki; Oku, Eijiro; Morishige, Satoshi; Takata, Yuka; Seki, Ritsuko; Osaki, Koichi; Hashiguchi, Michitoshi; Yoshimoto, Koji; Ohshima, Koichi; Nagafuji, Koji; Okamura, Takashi

    2013-01-01

    The small cell variant of anaplastic large cell lymphoma (ALCL) presents in a nearly identical manner to the more common ALK(+) primary ALCL, with the exception that it is more frequently associated with leukemic involvement, and the prognosis has been reported to be poor. We report a 40-year-old Japanese male who was diagnosed with small cell variant ALCL with peripheral blood involvement stage IVB, age-adjusted international prognostic index 3. Conventional cytogenetics of the bone marrow aspirate specimen showed abnormal metaphases with the following karyotype: 47, XY, +X, t(2;5)(p23;q35). The patient was treated with acute lymphoblastic leukemia-oriented intensive chemotherapy. He underwent allogeneic peripheral blood stem cell transplantation from his HLA-DR1 locus mismatch sister. Prior to transplant, the patient had residual lymphadenopathy considered to be in partial remission. As of August 2012, the patient has achieved 18 months of continuous complete remission (CCR), with a Karnofsky score of 100 %. We have identified a total of seven cases of small cell variant ALCL treated with allogeneic hematopoietic stem cell transplantation (HSCT) in the literature. Of these, no relapse was reported, and four patients were CCR more than 1 year. Allogeneic HSCT appears to represent a promising treatment option for small cell variant ALCL. PMID:23264126

  3. Tax unleashed: fulminant Tax-positive Adult T-cell Leukemia/Lymphoma after failed allogeneic stem cell transplantation.

    PubMed

    Ghez, David; Renand, Amédée; Lepelletier, Yves; Sibon, David; Suarez, Felipe; Rubio, Marie-Thérèse; Delarue, Richard; Buzyn, Agnès; Beljord, Kheira; Tanaka, Yuetsu; Varet, Bruno; Hermine, Olivier

    2009-12-01

    The human retrovirus HTLV-1 causes Adult T-cell Leukemia/Lymphoma (ATLL), a malignant lymphoproliferative disease of CD4+ T cells of dismal prognosis, in 3-5% of the 20 million infected individuals (Proietti et al.(1) and Bazarbachi et al.(2)). Infection with HTLV-1 represents a prototypical model of virus-mediated oncogenesis by virtue of the viral transactivator Tax, a potent oncogenic protein that exerts pleiotropic effects through its ability to deregulate the transcription of various cellular genes and signal transduction pathways and inhibit DNA repair enzymes, which are critical for T-cell homeostasis and genetic stability (Matsuoka and Jeang(3)) (et Boxus Retrovirology 2009). However, the oncogenic potential of Tax remains a conundrum. Tax protein expression is undetectable using conventional methods in freshly harvested ATLL cells and in non-malignant infected CD4+ T cells (Furukawa et al.(4)) but is up regulated after only a few hours of culture in vitro (Hanon et al.(5)). These observations strongly suggest that a host-derived mechanism is able to either actively repress the transcription of viral proteins in vivo or refrain the emergence of Tax-expressing cells, which would have a growth advantage. We report herein a unique case of CD4+ T-cell leukemia highly expressing Tax following rejection of an allogenic peripheral blood stem cell graft for an HTLV-1 associated lymphoma. PMID:19836302

  4. Multiple extramedullary relapses without bone marrow involvement after second allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.

    PubMed

    Yoo, Sang Woo; Chung, Eun Jin; Kim, Sun Young; Ko, Jeong Hee; Baek, Hey Sung; Lee, Hyun Ju; Oh, Sung Hee; Jeon, Seok Cheol; Lee, Woong Soo; Park, Chan Kum; Lee, Chul Hoon

    2012-06-01

    EMR without BM involvement after allogeneic HSCT is extremely rare, especially in children; only a few cases have been reported. A two-yr-old boy was diagnosed with AML (M4) and underwent allogeneic HSCT in first complete remission with BM from HLA-matched unrelated donor without GVHD. Four yr later, he had a BM relapse and after induction and consolidation chemotherapy, he received a second HSCT from an unrelated donor using peripheral blood stem cells. His second post-transplant course was complicated by extensive chronic GVHD involving the skin, oral cavity, and lungs, which was treated with tacrolimus and corticosteroid. Two yr later, he noticed a mild swelling in the right cheek area. The BM showed a complete remission marrow and a soft tissue biopsy was compatible with granulocytic sarcoma. PET-CT showed multifocal bone involvements. He received chemotherapy, and the chloromas decreased in size. We report a case of diffuse EMR of AML without BM involvement after a second allogeneic HSCT. PMID:21923886

  5. Influence of Previous Inflammatory Bowel Disease on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Matched-Pair Analysis.

    PubMed

    Rabian, Florence; Porcher, Raphael; Sicre de Fontbrune, Flore; Lioure, Bruno; Laplace, Anne; Nguyen, Stephanie; Tabrizi, Reza; Vigouroux, Stephane; Tomowiak, Cécile; Maillard, Nathalie; Suarez, Felipe; Delage, Jeremy; Peffault de Latour, Régis; Socié, Gérard

    2016-09-01

    The idiopathic inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis are associated with increased risk of hematologic malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) could be a curative strategy in this setting, but has been thought to be associated with increased nonrelapse mortality (NRM). We conducted a national French retrospective analysis of patients with IBD who underwent allogeneic HSCT for hematologic malignancies and were matched with 3 controls according to recipient, donor, and transplant characteristics. Between 2004 and 2015, 18 patients with IBD underwent allogeneic HSCT. With a median follow-up of 33 months for the patients with IBD and 57 months for controls, the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 39% for the patients with IBD and 40% for controls (hazard ratio [HR], 1.10; P = .82). The cumulative incidence of chronic GVHD at 48 months was 52% for the patients with IBD and 43% for controls (HR, 0.92; P = .89). Nonrelapse mortality at 48 months was 19% for the patients with IBD and 11% for controls (HR, 4.93; P = .067). Overall survival at 48 months was 59% for the patients with IBD and 60% for matched controls (HR, 1.35; P = .56). In conclusion, IBD should not be considered a contraindication for transplantation, and its impact on comorbidity indexes should be reduced. PMID:27246370

  6. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia

    PubMed Central

    Kayser, S; Benner, A; Thiede, C; Martens, U; Huber, J; Stadtherr, P; Janssen, J W G; Röllig, C; Uppenkamp, M J; Bochtler, T; Hegenbart, U; Ehninger, G; Ho, A D; Dreger, P; Krämer, A

    2016-01-01

    The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89% P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD. PMID:27471865

  7. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen.

    PubMed

    Boztug, Heidrun; Karitnig-Weiß, Cäcilia; Ausserer, Bernd; Renner, Ellen D; Albert, Michael H; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H; Mann, Georg; Horcher, Ernst; Rümmele-Waibel, Alexandra; Geyeregger, Rene; Lakatos, Karoly; Peters, Christina; Lawitschka, Anita; Matthes-Martin, Susanne

    2012-10-01

    Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality. PMID:22897717

  8. Allogeneic clonal mesenchymal stem cell therapy for refractory graft-versus-host disease to standard treatment: a phase I study.

    PubMed

    Yi, Hyeon Gyu; Yahng, Seung-Ah; Kim, Inho; Lee, Je-Hwan; Min, Chang-Ki; Kim, Jun Hyung; Kim, Chul Soo; Song, Sun U

    2016-01-01

    Severe graft-versus-host disease (GVHD) is an often lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). The safety of clinical-grade mesenchymal stem cells (MSCs) has been validated, but mixed results have been obtained due to heterogeneity of the MSCs. In this phase I study, the safety of bone marrow-derived homogeneous clonal MSCs (cMSCs) isolated by a new subfractionation culturing method was evaluated. cMSCs were produced in a GMP facility and intravenously administered to patients who had refractory GVHD to standard treatment resulting after allogeneic HSCT for hematologic malignancies. After administration of a single dose (1×10(6) cells/kg), 11 patients were evaluated for cMSC treatment safety and efficacy. During the trial, nine patients had 85 total adverse events and the rate of serious adverse events was 27.3% (3/11 patients). The only one adverse drug reaction related to cMSC administration was grade 2 myalgia in one patient. Treatment response was observed in four patients: one with acute GVHD (partial response) and three with chronic GVHD. The other chronic patients maintained stable disease during the observation period. This study demonstrates single cMSC infusion to have an acceptable safety profile and promising efficacy, suggesting that we can proceed with the next stage of the clinical trial. PMID:26807024

  9. An overview of infectious complications after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Sahin, Ugur; Toprak, Selami Kocak; Atilla, Pinar Ataca; Atilla, Erden; Demirer, Taner

    2016-08-01

    Infections are the most common and significant cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The presence of neutropenia and mucosal damage are the leading risk factors in the early pre-engraftment phase. In the early post-engraftment phase, graft versus host disease (GvHD) induced infection risk is increased in addition to catheter related infections. In the late phase, in which reconstitution of cellular and humoral immunity continues, as well as the pathogens seen during the early post-engraftment phase, varicella-zoster virus and encapsulated bacterial infections due to impaired opsonization are observed. An appropriate vaccination schedule following the cessation of immunosuppressive treatment after transplantation, intravenous immunoglobulin administration, and antimicrobial prophylaxis with penicillin or macrolide antibiotics during immunosuppressive treatment for GvHD might decrease the risk of bacterial infections. Older age, severe mucositis due to toxicity of chemotherapy, gastrointestinal tract colonization, prolonged neutropenia, unrelated donor and cord blood originated transplantations, acute and chronic GvHD are among the most indicative clinical risk factors for invasive fungal infections. Mold-active anti-fungal prophylaxis is suggested regardless of the period of transplantation among high risk patients. The novel serological methods, including Aspergillus galactomannan antigen and beta-D-glucan detection and computed tomography are useful in surveillance. Infections due to adenovirus, influenza and respiratory syncytial virus are encountered in all phases after allo-HSCT, including pre-engraftment, early post-engraftment and late phases. Infections due to herpes simplex virus-1 and -2 are mostly seen during the pre-engraftment phase, whereas, infections due to cytomegalovirus and human herpes virus-6 are seen in the early post-engraftment phase and Epstein-Barr virus and varicella

  10. Interplay between human microglia and neural stem/progenitor cells in an allogeneic co-culture model.

    PubMed

    Liu, Jia; Hjorth, Erik; Zhu, Mingqin; Calzarossa, Cinzia; Samuelsson, Eva-Britt; Schultzberg, Marianne; Åkesson, Elisabet

    2013-11-01

    Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-β was increased suggesting anti-inflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.

  11. Tenogenically Induced Allogeneic Mesenchymal Stem Cells for the Treatment of Proximal Suspensory Ligament Desmitis in a Horse

    PubMed Central

    Vandenberghe, Aurélie; Broeckx, Sarah Y.; Beerts, Charlotte; Seys, Bert; Zimmerman, Marieke; Verweire, Ineke; Suls, Marc; Spaas, Jan H.

    2015-01-01

    Suspensory ligament injuries are a common injury in sport horses, especially in competing dressage horses. Because of the poor healing of chronic recalcitrant tendon injuries, this represents a major problem in the rehabilitation of sport horses and often compromises the return to the initial performance level. Stem cells are considered as a novel treatment for different pathologies in horses and humans. Autologous mesenchymal stem cells (MSCs) are well known for their use in the treatment of tendinopathies; however, recent studies report a safe use of allogeneic MSCs for different orthopedic applications in horses. Moreover, it has been reported that pre-differentiation of MSCs prior to injection might result in improved clinical outcomes. For all these reasons, the present case report describes the use of allogeneic tenogenically induced peripheral blood-derived MSCs for the treatment of a proximal suspensory ligament injury. During conservative management for 4 months, the horse demonstrated no improvement of a right front lameness with a Grade 2/5 on the American Association of Equine Practitioners (AAEP) scale and a clear hypo-echoic area detectable in 30% of the cross sectional area. From 4 weeks after treatment, the lameness reduced to an AAEP Grade 1/5 and a clear filling of the lesion could be noticed on ultrasound. At 12 weeks (T4) after the first injection, a second intralesional injection with allogeneic tenogenically induced MSCs and platelet-rich plasma was given and at 4 weeks after the second injection (T5), the horse trotted sound under all circumstances with a close to total fiber alignment. The horse went back to previous performance level at 32 weeks after the first regenerative therapy and is currently still doing so (i.e., 20 weeks later or 1 year after the first stem cell treatment). In conclusion, the present case report demonstrated a positive evolution of proximal suspensory ligament desmitis after treatment with allogeneic

  12. Tenogenically Induced Allogeneic Mesenchymal Stem Cells for the Treatment of Proximal Suspensory Ligament Desmitis in a Horse.

    PubMed

    Vandenberghe, Aurélie; Broeckx, Sarah Y; Beerts, Charlotte; Seys, Bert; Zimmerman, Marieke; Verweire, Ineke; Suls, Marc; Spaas, Jan H

    2015-01-01

    Suspensory ligament injuries are a common injury in sport horses, especially in competing dressage horses. Because of the poor healing of chronic recalcitrant tendon injuries, this represents a major problem in the rehabilitation of sport horses and often compromises the return to the initial performance level. Stem cells are considered as a novel treatment for different pathologies in horses and humans. Autologous mesenchymal stem cells (MSCs) are well known for their use in the treatment of tendinopathies; however, recent studies report a safe use of allogeneic MSCs for different orthopedic applications in horses. Moreover, it has been reported that pre-differentiation of MSCs prior to injection might result in improved clinical outcomes. For all these reasons, the present case report describes the use of allogeneic tenogenically induced peripheral blood-derived MSCs for the treatment of a proximal suspensory ligament injury. During conservative management for 4 months, the horse demonstrated no improvement of a right front lameness with a Grade 2/5 on the American Association of Equine Practitioners (AAEP) scale and a clear hypo-echoic area detectable in 30% of the cross sectional area. From 4 weeks after treatment, the lameness reduced to an AAEP Grade 1/5 and a clear filling of the lesion could be noticed on ultrasound. At 12 weeks (T 4) after the first injection, a second intralesional injection with allogeneic tenogenically induced MSCs and platelet-rich plasma was given and at 4 weeks after the second injection (T 5), the horse trotted sound under all circumstances with a close to total fiber alignment. The horse went back to previous performance level at 32 weeks after the first regenerative therapy and is currently still doing so (i.e., 20 weeks later or 1 year after the first stem cell treatment). In conclusion, the present case report demonstrated a positive evolution of proximal suspensory ligament desmitis after treatment with allogeneic

  13. In Vivo Tracking of Systemically Administered Allogeneic Bone Marrow Mesenchymal Stem Cells in Normal Rats through Bioluminescence Imaging

    PubMed Central

    Cao, Juan; Hou, Shike; Ding, Hui; Liu, Ziquan; Song, Meijuan; Qin, Xiaojing; Wang, Xue; Yu, Mengyang; Sun, Zhiguang; Liu, Jinyang; Sun, Shuli; Xiao, Peixin

    2016-01-01

    Recently, mesenchymal stem cells (MSCs) are increasingly used as a panacea for multiple types of disease short of effective treatment. Dozens of clinical trials published demonstrated strikingly positive therapeutic effects of MSCs. However, as a specific agent, little research has focused on the dynamic distribution of MSCs after in vivo administration. In this study, we track systemically transplanted allogeneic bone marrow mesenchymal stem cells (BMSCs) in normal rats through bioluminescence imaging (BLI) in real time. Ex vivo organ imaging, immunohistochemistry (IHC), and RT-PCR were conducted to verify the histological distribution of BMSCs. Our results showed that BMSCs home to the dorsal skin apart from the lungs and kidneys after tail vein injection and could not be detected 14 days later. Allogeneic BMSCs mainly appeared not at the parenchymatous organs but at the subepidermal connective tissue and adipose tissue in healthy rats. There were no significant MSCs-related adverse effects except for transient decrease in neutrophils. These findings will provide experimental evidences for a better understanding of the biocharacteristics of BMSCs.

  14. In Vivo Tracking of Systemically Administered Allogeneic Bone Marrow Mesenchymal Stem Cells in Normal Rats through Bioluminescence Imaging.

    PubMed

    Cao, Juan; Hou, Shike; Ding, Hui; Liu, Ziquan; Song, Meijuan; Qin, Xiaojing; Wang, Xue; Yu, Mengyang; Sun, Zhiguang; Liu, Jinyang; Sun, Shuli; Xiao, Peixin; Lv, Qi; Fan, Haojun

    2016-01-01

    Recently, mesenchymal stem cells (MSCs) are increasingly used as a panacea for multiple types of disease short of effective treatment. Dozens of clinical trials published demonstrated strikingly positive therapeutic effects of MSCs. However, as a specific agent, little research has focused on the dynamic distribution of MSCs after in vivo administration. In this study, we track systemically transplanted allogeneic bone marrow mesenchymal stem cells (BMSCs) in normal rats through bioluminescence imaging (BLI) in real time. Ex vivo organ imaging, immunohistochemistry (IHC), and RT-PCR were conducted to verify the histological distribution of BMSCs. Our results showed that BMSCs home to the dorsal skin apart from the lungs and kidneys after tail vein injection and could not be detected 14 days later. Allogeneic BMSCs mainly appeared not at the parenchymatous organs but at the subepidermal connective tissue and adipose tissue in healthy rats. There were no significant MSCs-related adverse effects except for transient decrease in neutrophils. These findings will provide experimental evidences for a better understanding of the biocharacteristics of BMSCs. PMID:27610137

  15. In Vivo Tracking of Systemically Administered Allogeneic Bone Marrow Mesenchymal Stem Cells in Normal Rats through Bioluminescence Imaging

    PubMed Central

    Cao, Juan; Hou, Shike; Ding, Hui; Liu, Ziquan; Song, Meijuan; Qin, Xiaojing; Wang, Xue; Yu, Mengyang; Sun, Zhiguang; Liu, Jinyang; Sun, Shuli; Xiao, Peixin

    2016-01-01

    Recently, mesenchymal stem cells (MSCs) are increasingly used as a panacea for multiple types of disease short of effective treatment. Dozens of clinical trials published demonstrated strikingly positive therapeutic effects of MSCs. However, as a specific agent, little research has focused on the dynamic distribution of MSCs after in vivo administration. In this study, we track systemically transplanted allogeneic bone marrow mesenchymal stem cells (BMSCs) in normal rats through bioluminescence imaging (BLI) in real time. Ex vivo organ imaging, immunohistochemistry (IHC), and RT-PCR were conducted to verify the histological distribution of BMSCs. Our results showed that BMSCs home to the dorsal skin apart from the lungs and kidneys after tail vein injection and could not be detected 14 days later. Allogeneic BMSCs mainly appeared not at the parenchymatous organs but at the subepidermal connective tissue and adipose tissue in healthy rats. There were no significant MSCs-related adverse effects except for transient decrease in neutrophils. These findings will provide experimental evidences for a better understanding of the biocharacteristics of BMSCs. PMID:27610137

  16. Development of Tumor-Reactive T Cells After Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplant for Chronic Lymphocytic Leukemia

    PubMed Central

    Nishida, Tetsuya; Hudecek, Michael; Kostic, Ana; Bleakley, Marie; Warren, Edus H.; Maloney, David; Storb, Rainer; Riddell, Stanley R.

    2009-01-01

    Purpose Allogeneic NM-HSCT can result in durable remission of chronic lymphocytic leukemia (CLL). It is thought that the efficacy of NM-HSCT is mediated by recognition of tumor cells by T cells in the donor stem cell graft. We evaluated the development of cytotoxic T lymphocytes (CTL) specific for CLL after NM-HSCT to determine if their presence correlated with antitumor efficacy. Experimental Design Peripheral blood mononuclear cells obtained from twelve transplant recipients at intervals after NM-HSCT were stimulated in vitro with CLL cells. Polyclonal T cell lines and CD8+ T cell clones were derived from these cultures and evaluated for lysis of donor and recipient target cells including CLL. The presence and specificity of responses was correlated with clinical outcomes. Results Eight of the 12 patients achieved remission or a major antitumor response and all eight developed CD8+ and CD4+ T cells specific for antigens expressed by CLL. A clonal analysis of the CD8+ T cell response identified T cells specific for multiple minor histocompatibility (H) antigens expressed on CLL in six of the responding patients. A significant fraction of the CD8+ T cell response in some patients was also directed against non-shared tumor-specific antigens. By contrast, CLL-reactive T cells were not detected in the four patients who had persistent CLL after NM-HSCT, despite the development of GVHD. Conclusions The development of a diverse T cell response specific for minor H and tumor-associated antigens expressed by CLL predicts an effective GVL response after NM-HSCT. PMID:19567591

  17. Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kheav, Vissal David; Busson, Marc; Scieux, Catherine; Peffault de Latour, Régis; Maki, Guitta; Haas, Philippe; Mazeron, Marie-Christine; Carmagnat, Maryvonnick; Masson, Emeline; Xhaard, Aliénor; Robin, Marie; Ribaud, Patricia; Dulphy, Nicolas; Loiseau, Pascale; Charron, Dominique; Socié, Gérard; Toubert, Antoine; Moins-Teisserenc, Hélène

    2014-12-01

    Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T cells. We prospectively investigated natural killer-cell reconstitution in a cohort of 439 adult recipients who underwent non-T-cell-depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of graft-versus-host disease, and profiles of cytomegalovirus reactivation. In multivariate analysis we found that the absolute numbers of CD56(bright) natural killer cells at month 3 were significantly higher after myeloablative conditioning than after reduced intensity conditioning. Acute graft-versus-host disease impaired reconstitution of total and CD56(dim) natural killer cells at month 3. In contrast, high natural killer cell count at month 3 was associated with a lower incidence of chronic graft-versus-host disease, independently of a previous episode of acute graft-versus-host disease and stem cell source. NKG2C(+)CD56(dim) and total natural killer cell counts at month 3 were lower in patients with reactivation of cytomegalovirus between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced later cytomegalovirus reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

  18. Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Kheav, Vissal David; Busson, Marc; Scieux, Catherine; de Latour, Régis Peffault; Maki, Guitta; Haas, Philippe; Mazeron, Marie-Christine; Carmagnat, Maryvonnick; Masson, Emeline; Xhaard, Aliénor; Robin, Marie; Ribaud, Patricia; Dulphy, Nicolas; Loiseau, Pascale; Charron, Dominique; Socié, Gérard; Toubert, Antoine; Moins-Teisserenc, Hélène

    2014-01-01

    Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T cells. We prospectively investigated natural killer-cell reconstitution in a cohort of 439 adult recipients who underwent non-T-cell-depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of graft-versus-host disease, and profiles of cytomegalovirus reactivation. In multivariate analysis we found that the absolute numbers of CD56bright natural killer cells at month 3 were significantly higher after myeloablative conditioning than after reduced intensity conditioning. Acute graft-versus-host disease impaired reconstitution of total and CD56dim natural killer cells at month 3. In contrast, high natural killer cell count at month 3 was associated with a lower incidence of chronic graft-versus-host disease, independently of a previous episode of acute graft-versus-host disease and stem cell source. NKG2C+CD56dim and total natural killer cell counts at month 3 were lower in patients with reactivation of cytomegalovirus between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced later cytomegalovirus reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation. PMID:25085354

  19. [Allogenic hematopoietic stem cell transplantation with unrelated cord blood: report of three cases from the Chilean cord blood bank].

    PubMed

    Barriga, Francisco; Wietstruck, Angélica; Rojas, Nicolás; Bertin, Pablo; Pizarro, Isabel; Carmona, Amanda; Guilof, Alejandro; Rojas, Iván; Oyarzún, Enrique

    2013-08-01

    Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

  20. Chimerism of allogeneic mesenchymal cells in bone marrow, liver, and spleen after mesenchymal stem cells infusion.

    PubMed

    Meleshko, Alexander; Prakharenia, Irina; Kletski, Semen; Isaikina, Yanina

    2013-12-01

    Although an infusion of culture-expanded MSCs is applied in clinic to improve results of HSCs transplantation and for a treatment of musculoskeletal disorders, homing, and engraftment potential of culture-expanded MSC in humans is still obscure. We report two female patients who received allogeneic BM transplantation as a treatment of hematological diseases and a transplantation of MSCs from third-party male donors. Both patients died within one yr of infectious complications. Specimens of paraffin-embedded blocks of tissues from transplanted patients were taken. The aim of the study was to estimate possible homing and engraftment of allogeneic BM-derived MSCs in some tissues/organs of recipient. Sensitive real-time quantitative PCR analysis was applied with SRY gene as a target. MSC chimerism was found in BM, liver, and spleen of both patients. We conclude that sensitive RQ-PCR analysis is acceptable for low-level chimerism evaluation even in paraffin-embedded tissue specimens.

  1. Preclinical Study of Cell Therapy for Osteonecrosis of the Femoral Head with Allogenic Peripheral Blood-Derived Mesenchymal Stem Cells

    PubMed Central

    Fu, Qiang; Tang, Ning-Ning; Zhang, Qian; Liu, Yi; Peng, Jia-Chen; Fang, Ning; Yu, Li-Mei; Liu, Jin-Wei

    2016-01-01

    Purpose To explore the value of transplanting peripheral blood-derived mesenchymal stem cells from allogenic rabbits (rPBMSCs) to treat osteonecrosis of the femoral head (ONFH). Materials and Methods rPBMSCs were separated/cultured from peripheral blood after granulocyte colony-stimulating factor mobilization. Afterwards, mobilized rPBMSCs from a second passage labeled with PKH26 were transplanted into rabbit ONFH models, which were established by liquid nitrogen freezing, to observe the effect of rPBMSCs on ONFH repair. Then, the mRNA expressions of BMP-2 and PPAR-γ in the femoral head were assessed by RT-PCR. Results After mobilization, the cultured rPBMSCs expressed mesenchymal markers of CD90, CD44, CD29, and CD105, but failed to express CD45, CD14, and CD34. The colony forming efficiency of mobilized rPBMSCs ranged from 2.8 to 10.8 per million peripheral mononuclear cells. After local transplantation, survival of the engrafted cells reached at least 8 weeks. Therein, BMP-2 was up-regulated, while PPAR-γ mRNA was down-regulated. Additionally, bone density and bone trabeculae tended to increase gradually. Conclusion We confirmed that local transplantation of rPBMSCs benefits ONFH treatment and that the beneficial effects are related to the up-regulation of BMP-2 expression and the down-regulation of PPAR-γ expression. PMID:27189298

  2. Chronic active Epstein-Barr virus infection with marked pericardial effusion successfully treated with allogeneic peripheral blood stem cell transplantation.

    PubMed

    Matsui, Shinichiro; Takeda, Yusuke; Isshiki, Yusuke; Yamazaki, Atsuko; Nakao, Sanshiro; Takaishi, Koji; Nagao, Yuhei; Hasegawa, Nagisa; Togasaki, Emi; Shimizu, Ryoh; Kawajiri, Chika; Sakai, Shio; Mimura, Naoya; Takeuchi, Masahiro; Ohwada, Chikako; Sakaida, Emiko; Iseki, Tohru; Imadome, Ken-Ichi; Nakaseko, Chiaki

    2016-05-01

    A 23-year-old woman presented with a persistent fever and shortness of breath. Computed tomography showed marked pericardial effusion, hepatosplenomegaly, and cervical and mediastinal lymph node swelling. Epstein-Barr virus (EBV) antibody titers were abnormally elevated, and the copy number of EBV-DNA was increased in peripheral blood. Based on these observations, she was diagnosed with chronic active EBV infection (CAEBV). The EBV-infected cells in her peripheral blood were CD4(+)T lymphocytes. Fever and pericardial effusion improved following treatment with a combination of prednisolone, etoposide, and cyclosporine; however, peripheral blood EBV-DNA levels remained high. The patient underwent allogeneic peripheral blood stem cell transplantation from an EBV-seronegative, HLA-matched sibling donor, with fludarabine and melphalan conditioning. The post-transplantation course was uneventful, except for mild skin acute graft-versus-host disease (grade 2). EBV-DNA became undetectable in peripheral blood 98 days post transplantation. She has since been in good health without disease recurrence. CAEBV is a potentially fatal disease caused by persistent EBV infection of T lymphocytes or natural killer cells, thus requiring prompt treatment and allogeneic transplantation. Pericardial effusion is rarely observed in CAEBV and can impede its diagnosis. Therefore, we should be aware that patients may present with marked pericardial effusion as an initial manifestation of CAEBV. PMID:27263789

  3. Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant

    PubMed Central

    SONG, NINGXIA; GAO, LEI; QIU, HUIYING; HUANG, CHONGMEI; CHENG, HUI; ZHOU, HONG; LV, SHUQING; CHEN, LI; WANG, JIANMIN

    2015-01-01

    The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft-versus-host disease (aGVHD). However, the role of MSCs in graft-versus-leukemia remains to be determined. In the present study, we co-cultured C57BL/6 mouse bone marrow (BM)-derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit-8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)-10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies. PMID:25901937

  4. Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mostoufi-Moab, Sogol; Ginsberg, Jill P; Bunin, Nancy; Zemel, Babette; Shults, Justine; Leonard, Mary B

    2012-04-01

    Children requiring allogeneic hematopoietic stem cell transplantation (alloHSCT) have multiple risk factors for impaired bone accrual. The impact of alloHSCT on volumetric bone mineral density (vBMD) and cortical structure has not been addressed. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained in 55 alloHSCT recipients, ages 5 to 26 years, a median of 7 (range, 3-16) years after alloHSCT. pQCT outcomes were converted to sex- and race- specific Z-scores relative to age based on reference data in >700 concurrent healthy participants. Cortical section modulus (Zp; a summary measure of cortical bone structure and strength), and muscle and fat area Z-scores were further adjusted for tibia length for age Z-scores. AlloHSCT survivors had lower height Z-scores (-1.21 ± 1.25 versus 0.23 ± 0.92; p < 0.001), versus reference participants; BMI Z-scores did not differ. AlloHSCT survivors had lower trabecular vBMD (-1.05; 95% confidence interval [CI], -1.33 to -0.78; p < 0.001), cortical Zp (-0.63; 95% CI, -0.91 to -0.35; p < 0.001), and muscle (-1.01; 95% CI, -1.30 to -0.72; p < 0.001) Z-scores and greater fat (0.82; 95% CI, 0.54-1.11; p < 0.001) Z-scores, versus reference participants. Adjustment for muscle deficits eliminated Zp deficits in alloHSCT. Total body irradiation (TBI) was associated with lower trabecular vBMD (-1.30 ± 1.40 versus -0.49 ± 0.88; p = 0.01) and muscle (-1.34 ± 1.42 versus -0.34 ± 0.87; p < 0.01) Z-scores. Growth hormone deficiency (GHD) was associated with lower Zp Z-scores (-1.64 ± 2.47 versus -0.28 ± 1.24; p = 0.05); however, muscle differences were not significant (-1.69 ± 1.84 versus -0.78 ± 1.01; p = 0.09). History of graft versus host disease was not associated with pQCT outcomes. In summary, alloHSCT was associated with significant deficits in trabecular vBMD, cortical geometry, and muscle area years after transplantation. TBI and

  5. Psychosocial aspects of haematopoietic stem cell donation for allogeneic transplantation: how family donors cope with this experience.

    PubMed

    Munzenberger, N; Fortanier, C; Macquart-Moulin, G; Faucher, C; Novakovitch, G; Maraninchi, D; Moatti, J P; Blaise, D

    1999-01-01

    Peripheral blood stem cell (PBSC) allogeneic transplantation is an innovative medical procedure which has many advantages in comparison with bone marrow (BM) transplantation, but it involves administering haematopoietic growth factors (HGFs) to donors, the long-term physiological effects of which have not yet been established. The main aim of the present study was to analyse how family PBSC donors cope when confronted with this particular risk context. In addition to data collected on the personal and social aspects of the donors' experience, questionnaires were used to measure their quality of life (pain and anxiety) before, during and after donation, and they were subsequently interviewed in depth by a psychologist. Twenty-two donors participated in this study. They did not all react to the experience of blood cell donation in the same way, in terms of their own personal feelings, attitudes towards the donation, their relationships with the other members of the family, and their awareness of the risk involved. PMID:10202783

  6. The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study

    PubMed Central

    Klusmann, Jan-Henning; Reinhardt, Dirk; Zimmermann, Martin; Kremens, Bernhard; Vormoor, Josef; Dworzak, Michael; Creutzig, Ursula; Klingebiel, Thomas

    2012-01-01

    Background The role of allogeneic stem cell transplantation in post-remission management of children with high-risk acute myeloid leukemia remains controversial. In the multi-center AML-BFM 98 study we prospectively evaluated the impact of allogeneic stem cell transplantation in children with high-risk acute myeloid leukemia in first complete remission. Design and Methods HLA-typed patients with high-risk acute myeloid leukemia, who achieved first complete remission (n=247), were included in this analysis. All patients received double induction and consolidation. Based on the availability of a matched-sibling donor, patients were allocated by genetic chance to allogeneic stem cell transplantation (n=61) or chemotherapy-only (i.e. intensification and maintenance therapy; n=186). The main analysis was done on an intention-to-treat basis according to this allocation. Results Intention-to-treat analysis did not show a significantly different 5-year disease-free survival (49±6% versus 45±4%, Plog rank=0.44) or overall survival (68±6% versus 57±4%, Plog rank=0.17) between the matched-sibling donor and no-matched-sibling donor groups, whereas late adverse effects occurred more frequently after allogeneic stem cell transplantation (72.5% versus 31.8%, PFischer<0.01). These results were confirmed by as-treated analysis corrected for the time until transplantation (5-year overall survival: 72±8% versus 60±4%, PMantel-Byar 0.21). Subgroup analysis demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic stem cell transplantation (5-year overall survival: 94±6% versus 52±7%, Plog-rank=0.01; n=18 versus 49) in contrast to patients without 11q23 aberrations (5-year overall survival: 58±8% versus 55±5%, Plog-rank=0.66). Conclusions Our analyses defined a genetic subgroup of children with high-risk acute myeloid leukemia who benefited from allogeneic stem cell transplantation in the prospective multi-center AML-BFM 98 study. For

  7. Safety of Live Attenuated High-Titer Varicella-Zoster Virus Vaccine in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

    PubMed

    Aoki, Takahiro; Koh, Katsuyoshi; Kawano, Yutaka; Mori, Makiko; Arakawa, Yuki; Kato, Motohiro; Hanada, Ryoji

    2016-04-01

    Hematopoietic stem cell transplantation (HSCT) recipients have a high risk of varicella-zoster virus (VZV) infections. Although VZV vaccination may be beneficial in preventing VZV infections, data on safety and efficacy of VZV vaccines in HSCT recipients, particularly of zoster vaccine, are limited. We report our experience with the use of a single dose of an Oka strain high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients. We administered the high-titer VZV vaccine to 31 pediatric allogeneic HSCT recipients without vaccine-type VZV infections. One patient developed varicella due to wild-type VZV 13 days after vaccination. No zoster developed after vaccination during a median follow-up period of 4.8 years from vaccination. No other adverse effects were observed. Eighteen of the 31 patients (58.1%) were seropositive after vaccination. Seventeen patients were vaccinated within 24 months after HSCT; the seropositivity of these patients did not significantly differ from that of patients vaccinated > 24 months after HSCT. VZV vaccination may be a safe and beneficial approach in preventing VZV infections after HSCT.

  8. DNA profiling in peripheral blood, buccal swabs, hair follicles and semen from a patient following allogeneic hematopoietic stem cells transplantation

    PubMed Central

    LI, YA-TING; XIE, MING-KUN; WU, JIN

    2014-01-01

    Allogeneic peripheral blood stem cells transplantation (allo-PBSCT) or allogeneic bone marrow transplantation (allo-BMT) have been widely used to treat patients exhibiting certain severe illnesses. However, previous studies have shown that the biological materials of allo-PBSCT or allo-BMT recipients may not constitute credible materials for personal identification. In the present study, four types of commonly used samples were collected from a male individual following gender-matched allo-BMT. Autosomal short tandem repeat (STR) and Y-STR markers analysis, based on polymerase chain reaction, were used to evaluate the chimerism status. The results showed that the blood sample were all donor type, the buccal swab sample were mixed chimerism, and the sperm and hair follicle samples maintained a recipient origin of 100%. In conclusion, identical results were obtained by the two methods and it was confirmed that DNA extracted from hair follicles and sperm can be used as a reference for the pre-transplant genotype DNA profile of the recipient in the gender-match allo-BMT or -PBSCT. PMID:25279149

  9. [Extramedullary relapse of acute lymphoblastic leukemia in the mastoid after allogeneic hematopoietic stem cell transplantation: a case report].

    PubMed

    Dong, Fangru; Wang, Na; Liu, Ruli

    2016-01-01

    Extramedullary relapse of acute lymphoblastic leukemia (ALL) in the mastoid after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare. In this paper, we describe such an uncommon case of extramedullary relapse of ALL in the mastoid. The patient, who had been diagnosed as having ALL and underwent an allo-HSCT from his matched sibling donor. Eight months after allo-HSCT, he presented with ear-ache, tinnitus. The middle ear mastoid CT revealed otomastoiditis. The patient underwent operation. After pathological examination, the definited diagnosis was made that the patient was extramedullary relapse of ALL in the mastoid. We should pay more attention to the patients with hemopathy, which can help to improve early diagnosis. PMID:27197463

  10. Quality of life, social challenges, and psychosocial support for long-term survivors after allogeneic hematopoietic stem-cell transplantation.

    PubMed

    Norkin, Maxim; Hsu, Jack W; Wingard, John R

    2012-01-01

    Over the last two decades quality of life (QoL) and the social challenges of allogeneic hematopoietic stem cell transplant (allo-HSCT) survivors have been emerging as subjects of extensive research and are now considered as very important aspects in the pretransplant evaluation and management of allo-HSCT recipients. Recognition of QoL challenges in allo-HSCT survivors allows timely interventions leading to improvement of post-transplant outcomes. It needs to be recognized that long-lasting life changes associated with survivorship after allo-HSCT also significantly affect QoL of partners of allo-HSCT survivors. Currently, resources should be focused on how research findings can be used by patients, their partners, and physicians to optimize QoL and psychosocial adjustment.

  11. Dose-independent confusion induced by voriconazole in a patient with Asian ancestry after allogeneic hematopoietic stem cell transplant.

    PubMed

    Hui, John

    2016-02-01

    This is the case of a 71-year-old man with Asian ancestry who had myelodysplastic syndrome admitted for allogeneic hematopoietic stem cell transplant. This case suggests that voriconazole-induced confusion is probably dose-independent and reversible with no residual symptoms after discontinuation of voriconazole. Patient can experience confusion even voriconazole is ordered according to package insert and serum voriconazole level is within therapeutic range (1-6 µg/mL). The onset of confusion can be delayed and sudden after seven days of voriconazole therapy. Genotyping of CYP2C19 can be tested for Asian populations since 15-20% of them could be poor metabolizers of voriconazole.

  12. Risk factors of Ganciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients.

    PubMed

    Venton, G; Crocchiolo, R; Fürst, S; Granata, A; Oudin, C; Faucher, C; Coso, D; Bouabdallah, R; Berger, P; Vey, N; Ladaique, P; Chabannon, C; le Merlin, M; Blaise, D; El-Cheikh, J

    2014-02-01

    Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III-IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III-IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25-5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125-0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11-5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.

  13. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

    PubMed Central

    Craddock, Charles; Labopin, Myriam; Robin, Marie; Finke, Juergen; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Bourhis, Jean Henri; Sengelov, Henrik; Blaise, Didier; Luft, Thomas; Hallek, Michael; Kröger, Nicolaus; Nagler, Arnon; Mohty, Mohamad

    2016-01-01

    Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%–37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required. PMID:27081178

  14. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia.

    PubMed

    Craddock, Charles; Labopin, Myriam; Robin, Marie; Finke, Juergen; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Bourhis, Jean Henri; Sengelov, Henrik; Blaise, Didier; Luft, Thomas; Hallek, Michael; Kröger, Nicolaus; Nagler, Arnon; Mohty, Mohamad

    2016-07-01

    Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%-37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required. PMID:27081178

  15. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency.

  16. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency. PMID:27602064

  17. Pentraxin-3 levels in graft-versus-host disease during allogeneic hematopoietic stem cell transplantation.

    PubMed

    Doehn, Jan-Moritz; Winkler, Andreas; Kuzmina, Zoya; Hladik, Anastasiya; Greinix, Hildegard; Knapp, Sylvia; Robak, Oliver

    2016-10-01

    Acute and chronic graft-versus-host-diseases (aGVHD and cGVHD, respectively) are serious complications after hematopoietic stem cell transplantation (HSCT), impairing survival and quality of life. Because the underlying pathomechanism of GVHD is still poorly understood, we investigated the novel inflammatory marker Pentraxin-3 (PTX3) for its potential role in acute and chronic GVHD compared with autologous HSCT and healthy individuals. We collected plasma samples from patients undergoing autologous (n = 12) and allogeneic (n = 28) HSCT and from healthy individuals (n = 15) throughout 7 days before and up to 1 year after HSCT. PTX3 levels in patients with aGVHD were significantly higher (36.4 ± 23.6 ng/mL) than in allogeneic patients without aGVHD (10.4 ± 4.4 ng/mL, p = 0.0001), autologous controls (11.4 ± 6.7 ng/mL, p = 0.001), or healthy individuals (1.9 ± 0.6 ng/mL, p < 0.001). PTX3 levels in patients with cGVHD (13.6 ± 6.3 ng/mL) were significantly lower than in allogeneic patients without cGVHD (25.1 ± 13.8 ng/mL, p = 0.04) and higher than in autologous controls (8.9 ± 7.8 ng/mL, p = 0.07) and healthy individuals (1.9 ± 0.6 ng/mL, p < 0.001). Severity of aGVHD and cGVHD correlated with PTX3 levels. Rising PTX3 levels after HSCT indicated unfavorable outcome. We show that PTX3 levels correlate with the severity of aGVHD, cGVHD, and-with reservations-survival in patients undergoing allogeneic HSCT.

  18. The EuroChimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation.

    PubMed

    Lion, T; Watzinger, F; Preuner, S; Kreyenberg, H; Tilanus, M; de Weger, R; van Loon, J; de Vries, L; Cavé, H; Acquaviva, C; Lawler, M; Crampe, M; Serra, A; Saglio, B; Colnaghi, F; Biondi, A; van Dongen, J J M; van der Burg, M; Gonzalez, M; Alcoceba, M; Barbany, G; Hermanson, M; Roosnek, E; Steward, C; Harvey, J; Frommlet, F; Bader, P

    2012-08-01

    Hematopoietic stem cell transplantation is becoming an increasingly important approach to treatment of different malignant and non-malignant disorders. There is thus growing demand for diagnostic assays permitting the surveillance of donor/recipient chimerism posttransplant. Current techniques are heterogeneous, rendering uniform evaluation and comparison of diagnostic results between centers difficult. Leading laboratories from 10 European countries have therefore performed a collaborative study supported by a European grant, the EuroChimerism Concerted Action, with the aim to develop a standardized diagnostic methodology for the detection and monitoring of chimerism in patients undergoing allogeneic stem cell transplantation. Following extensive analysis of a large set of microsatellite/short tandem repeat (STR) loci, the EuroChimerism (EUC) panel comprising 13 STR markers was established with the aim to optimally meet the specific requirements of quantitative chimerism analysis. Based on highly stringent selection criteria, the EUC panel provides multiple informative markers in any transplant setting. The standardized STR-PCR tests permit detection of donor- or recipient-derived cells at a sensitivity ranging between 0.8 and 1.6%. Moreover, the EUC assay facilitates accurate and reproducible quantification of donor and recipient hematopoietic cells. Wide use of the European-harmonized protocol for chimerism analysis presented will provide a basis for optimal diagnostic support and timely treatment decisions.

  19. Systemic and Local Administration of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells Promotes Fracture Healing in Rats.

    PubMed

    Huang, Shuo; Xu, Liangliang; Zhang, Yifeng; Sun, Yuxin; Li, Gang

    2015-01-01

    Mesenchymal stem cells (MSCs) are immune privileged and a cell source for tissue repair. Previous studies showed that there is systemic mobilization of osteoblastic precursors to the fracture site. We hypothesized that both systemic and local administration of allogeneic MSCs may promote fracture healing. Bone marrow-derived MSCs and skin fibroblasts were isolated from GFP Sprague-Dawley rats, cultured, and characterized. Closed transverse femoral fracture with internal fixation was established in 48 adult male Sprague-Dawley rats, which were randomly assigned into four groups receiving PBS injection, MSC systemic injection, fibroblast systemic injection, and MSC fracture site injection; 2 × 10(6) cells were injected at 4 days after fracture. All animals were sacrificed at 5 weeks after fracture; examinations included weekly radiograph, micro-CT, mechanical testing, histology, immunohistochemistry, and double immunofluorescence. The callus size of MSC injection groups was significantly larger among all the groups. Radiographs and 3D reconstruction images showed that the fracture gaps united in the MSC injected groups, while gaps were still seen in the fibroblast and PBS injection groups. The mechanical properties were significantly higher in the MSC injection groups than those in the fibroblast and PBS groups, but no difference was found between the MSC local and systemic injection groups. Immunohistochemistry and double immunofluorescence demonstrated that GFP-positive MSCs were present in the callus in the MSC injection groups at 5 weeks after fracture, and some differentiated into osteoblasts. Quantitative analysis revealed the number of GFP-positive cells in the callus in the MSC systemic injection group was significantly lower than that of the MSC local injection group. The proportion of GFP osteoblasts in GFP-positive cells in the MSC systemic injection group was significantly lower than that of the MSC local injection group. These findings provide critical

  20. [18F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

    PubMed Central

    Eissenberg, Linda G; Rettig, Michael P; Ritchey, Julie K; Prior, Julie L; Schwarz, Sally W; Frye, Jennifer; White, Brian S; Fulton, Robert S; Ghobadi, Armin; Cooper, Matthew L; Couriel, Daniel R; Seegulam, Muhammad Esa; Piwnica-Worms, David; Dehdashti, Farrokh; Cornetta, Kenneth; DiPersio, John F

    2015-01-01

    Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75+-selected donor T cells (1.0–13 × 105)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18F)fluoro-3-hydroxymethyl-butyl]guanine ([18F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [18F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [18F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. PMID:25807290

  1. Assessing the Influence of Different Comorbidities Indexes on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in a Developing Country

    PubMed Central

    Teixeira, Gustavo Machado; Bittencourt, Henrique; Rezende, Suely Meireles

    2015-01-01

    Although the application of Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) has enabled better prediction of transplant-related mortality (TRM) in allogeneic hematopoietic stem cell transplants (AHSCT), data from developing countries are scarce. This study prospectively evaluated the HCT-CI and the Adult Comorbidity Evaluation (ACE-27), in its original and in a modified version, as predictors of post-transplant complications in adults undergoing a first related or unrelated AHSCT in Brazil. Both bone marrow (BM) and peripheral blood stem cells (PBSC) as graft sources were included. We analyzed the cumulative incidence of granulocyte and platelet recovery, sinusoidal obstructive syndrome, acute and chronic graft-versus-host disease, relapse and transplant-related mortality, and rates of event-free survival and overall survival. Ninety-nine patients were assessed. Median age was 38 years (18–65 years); HCT-CI ≥ 3 accounted for only 8% of cases; hematologic malignancies comprised 75.8% of the indications for AHSCT. There was no association between the HCT-CI or the original or modified ACE-27 with TRM or any other studied outcomes after AHSCT. These results show that, in the population studied, none of the comorbidity indexes seem to be associated with AHSCT outcomes. A significantly low frequency of high-risk (HCT-CI ≥ 3) in this Brazilian population might justify these results. PMID:26394228

  2. Rabbit antithymocyte globulin (Thymoglobulin®) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients

    PubMed Central

    Na, Il-Kang; Wittenbecher, Friedrich; Dziubianau, Mikalai; Herholz, Anne; Mensen, Angela; Kunkel, Désirée; Blau, Olga; Blau, Igor; Thiel, Eckhard; Uharek, Lutz; Scheibenbogen, Carmen; Rieger, Kathrin; Thiel, Andreas

    2013-01-01

    Rabbit antithymocyte globulin-Genzyme™ is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme™ on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme™ during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme™ had almost undetectable levels of recent thymic emigrants (CD45RA+CD31+) of both conventional and regulatory CD4T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4+CD45RA-memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme™. In vitro, rabbit antithymocyte globulin-Genzyme™ induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius™. Rabbit antithymocyte globulin-Genzyme™ in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4+ T cells. The sustained depletion of conventional and regulatory CD4+T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme™ could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative. PMID:22801968

  3. The Impact of the German Tissue Act on the Manufacturing of Autologous and Allogeneic Stem Cell Preparations.

    PubMed

    Schlenke, Peter; Tapernon, Karin; Ahlke, Christoph; Mertens, Alexandra; Sibrowski, Walter

    2008-01-01

    SUMMARY: Cellular therapeutic agents considerably contribute to the optimal treatment of patients with hematological malignancies such as leukemia or nonhematological disorders. Over the last 50 years especially the transplantation of autologous and allogeneic stem cells from different sources after high-dose or myeloablative chemotherapy became a well-established standard therapy that cures or alleviates the symptoms in more than 50,000 patients/year worldwide. In the near future, the current progress in fundamental research on stem cells and immunobiology will allow for the clinical implementation of novel advanced cellular therapies, including gene therapeutic options. The European and German legislation have realized the need of international regulations for improved standardization and harmonization of stem cell transplants, associated cell-therapeutic agents as well as various tissue-engineered preparations in the emerging field of regenerative medicine. The Tissue Directive 2004/23/EC, issued and ratified by the European Parliament in March 2004, and its national transition into the German Tissue Act which came into force in July 2007 define the quality and safety standards for the donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells. These standards are of high relevance to ensure the efficient prevention of the transmission of viral and nonviral infectious pathogens and to achieve the same safeguards as in the population's blood supply. This review discusses the pros and cons of the new legislation and argues for keeping the administrative and regulative demands in reasonable limits and for offering innovative approaches of cellular therapies to the European citizens.

  4. The Role of Autologous and Allogeneic Stem Cell Transplantation in Follicular Lymphoma in The New Drugs Era.

    PubMed

    Maura, Francesco; Farina, Lucia; Corradini, Paolo

    2016-01-01

    Follicular lymphoma (FL) is the second most common histotype of non-Hodgkin's lymphoma, and it is generally characterized by a heterogeneous clinical course. Despite recent therapeutic and diagnostic improvements, a significant fraction of FL patients still relapsed. In younger and/or fit FL relapsed patients bone marrow transplant (BMT) has represented the main salvage therapy for many years. Thanks to the ability of high-dose chemotherapy to overcome the lymphoma resistance and refractoriness, autologous stem cell transplantation (ASCT) can achieve a high complete remission rate (CR) and favorable outcome regarding progression-free survival (PFS) and overall survival (OS). Allogeneic stem cell transplantation (alloSCT) combines the high dose chemotherapy effect together with the immune reaction of the donor immune system against lymphoma, the so-called 'graft versus lymphoma' (GVL) effect. Considering the generally higher transplant-related mortality (TRM), alloSCT is mostly indicated for FL relapsed after ASCT. During the last years, there have been a great spread of novel effective and feasible drugs Although these and future novel drugs will probably change our current approach to FL, the OS post-BMT (ASCT and alloSCT) has never been reproduced by any novel combination. In this scenario, it is important to correctly evaluate the disease status, the relapse risk and the comorbidity profile of the relapsed FL patients in order to provide the best salvage therapy and eventually transplant consolidation. PMID:27648208

  5. The Role of Autologous and Allogeneic Stem Cell Transplantation in Follicular Lymphoma in The New Drugs Era

    PubMed Central

    Maura, Francesco; Farina, Lucia; Corradini, Paolo

    2016-01-01

    Follicular lymphoma (FL) is the second most common histotype of non-Hodgkin’s lymphoma, and it is generally characterized by a heterogeneous clinical course. Despite recent therapeutic and diagnostic improvements, a significant fraction of FL patients still relapsed. In younger and/or fit FL relapsed patients bone marrow transplant (BMT) has represented the main salvage therapy for many years. Thanks to the ability of high-dose chemotherapy to overcome the lymphoma resistance and refractoriness, autologous stem cell transplantation (ASCT) can achieve a high complete remission rate (CR) and favorable outcome regarding progression-free survival (PFS) and overall survival (OS). Allogeneic stem cell transplantation (alloSCT) combines the high dose chemotherapy effect together with the immune reaction of the donor immune system against lymphoma, the so-called ‘graft versus lymphoma’ (GVL) effect. Considering the generally higher transplant-related mortality (TRM), alloSCT is mostly indicated for FL relapsed after ASCT. During the last years, there have been a great spread of novel effective and feasible drugs Although these and future novel drugs will probably change our current approach to FL, the OS post-BMT (ASCT and alloSCT) has never been reproduced by any novel combination. In this scenario, it is important to correctly evaluate the disease status, the relapse risk and the comorbidity profile of the relapsed FL patients in order to provide the best salvage therapy and eventually transplant consolidation. PMID:27648208

  6. The Role of Autologous and Allogeneic Stem Cell Transplantation in Follicular Lymphoma in The New Drugs Era

    PubMed Central

    Maura, Francesco; Farina, Lucia; Corradini, Paolo

    2016-01-01

    Follicular lymphoma (FL) is the second most common histotype of non-Hodgkin’s lymphoma, and it is generally characterized by a heterogeneous clinical course. Despite recent therapeutic and diagnostic improvements, a significant fraction of FL patients still relapsed. In younger and/or fit FL relapsed patients bone marrow transplant (BMT) has represented the main salvage therapy for many years. Thanks to the ability of high-dose chemotherapy to overcome the lymphoma resistance and refractoriness, autologous stem cell transplantation (ASCT) can achieve a high complete remission rate (CR) and favorable outcome regarding progression-free survival (PFS) and overall survival (OS). Allogeneic stem cell transplantation (alloSCT) combines the high dose chemotherapy effect together with the immune reaction of the donor immune system against lymphoma, the so-called ‘graft versus lymphoma’ (GVL) effect. Considering the generally higher transplant-related mortality (TRM), alloSCT is mostly indicated for FL relapsed after ASCT. During the last years, there have been a great spread of novel effective and feasible drugs Although these and future novel drugs will probably change our current approach to FL, the OS post-BMT (ASCT and alloSCT) has never been reproduced by any novel combination. In this scenario, it is important to correctly evaluate the disease status, the relapse risk and the comorbidity profile of the relapsed FL patients in order to provide the best salvage therapy and eventually transplant consolidation.

  7. Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases.

    PubMed

    Slatter, M A; Boztug, H; Pötschger, U; Sykora, K-W; Lankester, A; Yaniv, I; Sedlacek, P; Glogova, E; Veys, P; Gennery, A R; Peters, C

    2015-12-01

    An increasing number of children with non-malignant diseases can be cured by allogeneic haematopoietic stem cell transplantation (HSCT). Treosulfan (L-treitol-1,4-bis-methanesulfonate) is being used more frequently for conditioning, owing to its' lower toxicity profile compared with conventional myeloablative regimens. A retrospective analysis was performed of children registered in the EBMT database, who received treosulfan before HSCT between January 2005 and 2010, to identify possible dose-related toxicity and determine the incidence of engraftment, treatment-related mortality and overall survival (OS). Results from 316 transplants from 11 different countries are presented. Ninety-five (30%) were under 1 year of age at the time of transplant. OS was 83% and event-free survival was 76%; 3-year OS and event-free survival of infants below 1 year were 79% and 73%, respectively. No association was found with age at transplant, dose of treosulfan given, other agents used in combination with treosulfan, donor type, stem cell source, or second or subsequent transplant. In this report of the largest number of children to date receiving treosulfan for non-malignant diseases, treosulfan is shown to be a safe and effective agent even for those under 1 year of age at the time of transplant. Further prospective studies are needed using precisely defined protocols with pharmacokinetic monitoring and detailed chimerism analysis. In addition, long-term studies will be vital to determine long-term effects, for example, on fertility in comparison with other regimens.

  8. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes.

    PubMed

    Bassi, Ênio J; Moraes-Vieira, Pedro M M; Moreira-Sá, Carla S R; Almeida, Danilo C; Vieira, Leonardo M; Cunha, Cláudia S; Hiyane, Meire I; Basso, Alexandre S; Pacheco-Silva, Alvaro; Câmara, Niels O S

    2012-10-01

    Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.

  9. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes.

    PubMed

    Bassi, Ênio J; Moraes-Vieira, Pedro M M; Moreira-Sá, Carla S R; Almeida, Danilo C; Vieira, Leonardo M; Cunha, Cláudia S; Hiyane, Meire I; Basso, Alexandre S; Pacheco-Silva, Alvaro; Câmara, Niels O S

    2012-10-01

    Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D. PMID:22688334

  10. Clinical utility of chimerism status assessed by lineage-specific short tandem repeat analysis: experience from four cases of allogeneic stem cell transplantation.

    PubMed

    Goh, Ri-Young; Cho, Sung-Suk; Song, Yoo-Jeong; Heo, Kyeong; Oh, Sung-Yong; Kim, Sung-Hyun; Kwon, Hyeok-Chan; Kim, Hyo-Jin; Han, Jin-Yeong

    2009-08-01

    Chimerism testing permits early prediction and documentation of successful engraftment, and also facilitates detection of impending graft rejection. In this study, we serially monitored chimerism status by short tandem repeat-based PCR in nucleated cells (NC), T cells and natural killer (NK) cells after myeloablative allogeneic stem cell transplantation (SCT). Four patients with myeloid malignancies showed discrepant chimerism results among those three fractions. Three patients had mixed chimerism (MC) of donor/host T cells at a time point around the onset of chronic graft-versus-host disease (GVHD). In two patients with disease relapse, MC of NK cells preceded a morphological relapse or NK cells showed a higher percentage of patient cells compared to NC. Therefore, our study shows that chimerism analysis in lineage-specific cells might be useful in predicting clinical outcome after allogeneic SCT in certain patients.

  11. Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms

    PubMed Central

    2011-01-01

    A 54-year-old woman was diagnosed with infiltrative ductal breast carcinoma. Two years after treatment, the patient developed an acute myeloid leukemia (AML) which harbored del(11q23) in 8% of the blast cells. The patient was submitted for allogeneic stem cell transplantation (aSCT) from her HLA-compatible sister. Ten months after transplantation, she relapsed with an AML with basophilic maturation characterized by CD45low CD33high, CD117+, CD13-/+, HLA Drhigh, CD123high, and CD203c+ blast cells lacking expression of CD7, CD10, CD34, CD15, CD14, CD56, CD36, CD64, and cytoplasmic tryptase. Karyotype analysis showed the emergence of a new clone with t(2;14) and FISH analysis indicated the presence of MLL gene rearrangement consistent with del(11q23). Interestingly, AML blast cell DNA tested with microsatellite markers showed the same pattern as the donor's, suggesting that this AML emerged from donor cells. Additionally, polymorphisms of the XPA, XPD, XRCC1, XRCC3 and RAD51 DNA repair genes revealed three unfavorable alleles with low DNA repair capacity. In summary, we report the first case of AML involving XPD and XRCC3 polymorphisms from donor origin following allogeneic stem cell transplantation and highlight the potential need for careful analysis of DNA repair gene polymorphisms in selecting candidate donors prior to allogeneic stem cell transplantation. PMID:21951951

  12. Lineage-specific chimerism analysis in nucleated cells, T cells and natural killer cells after myeloablative allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Goh, Ri-Young; Kim, Sung-Hyun

    2011-01-01

    Background Chimerism analysis is an important tool for assessing the origin of hematopoietic cells after allogeneic stem cell transplantation (allo-SCT) and can be used to detect impending graft rejection and the recurrence of underlying malignant or nonmalignant diseases. Methods This study included 24 patients who underwent myeloablative allo-SCT. DNA was extracted from nucleated cells (NCs), T cells, and natural killer (NK) cells, and the chimerism status of these cell fractions was determined by STR-PCR performed using an automated fluorescent DNA analyzer. Results Twenty-three out of the 24 patients achieved engraftment. Mixed chimerism (MC) in NCs, but not in T cells and NK cells, was significantly correlated with disease relapse. MC in all cell fractions was correlated with mortality. Ten patients (41.6%) developed extensive chronic GVHD. Six patients had MC in T cells, and 3 of them had chronic GVHD. Four patients with MC and relapse received donor lymphocyte infusion (DLI), and among them, 3 had secondary relapse. Further, the chimerism status differed among different cell lineages in 6 patients with myeloid malignancies. Conclusion The implications of MC in lymphocyte subsets are an important area for future research. Chimerism analysis in lineage-specific cells permits detection of relapse and facilitates the monitoring of therapeutic interventions. These results can provide the basic data for chimerism analysis after myeloablative SCT. PMID:21461299

  13. Importance of killer immunoglobulin-like receptors in allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Franceschi, Danilo Santana Alessio; de Souza, Cármino Antonio; Aranha, Francisco José Penteado; Cardozo, Daniela Maira; Sell, Ana Maria; Visentainer, Jeane Eliete Laguila

    2011-01-01

    Hematopoietic stem cell transplantation is the treatment of choice for many hematologic diseases, such as multiple myeloma, bone marrow aplasia and leukemia. Human leukocyte antigen (HLA) compatibility is an important tool to prevent post-transplant complications such as graft rejection and graft-versus-host disease, but the high rates of relapse limit the survival of transplant patients. Natural Killer cells, a type of lymphocyte that is a key element in the defense against tumor cells, cells infected with viruses and intracellular microbes, have different receptors on their surfaces that regulate their cytotoxicity. Killer immunoglobulin-like receptors are the most important, interacting consistently with human leukocyte antigen class I molecules present in other cells and thus controlling the activation of natural killer cells. Several studies have shown that certain combinations of killer immunoglobulin-like receptors and human leukocyte antigens (in both donors and recipients) can affect the chances of survival of transplant patients, particularly in relation to the graft-versusleukemia effect, which may be associated to decreased relapse rates in certain groups. This review aims to shed light on the mechanisms and effects of killer immunoglobulin-like receptors - human leukocyte antigen associations and their implications following hematopoietic stem cell transplantation, and to critically analyze the results obtained by the studies presented herein. PMID:23284260

  14. Hyperthyroidism After Allogeneic Hematopoietic Stem Cell Transplantation: A Report of Four Cases

    PubMed Central

    Sağ, Erdal; Gönç, Nazlı; Alikaşifoğlu, Ayfer; Kuşkonmaz, Barış; Uçkan, Duygu; Özön, Alev; Kandemir, Nurgün

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many hematological disorders, primary immunodeficiencies, and metabolic disorders. Thyroid dysfunction is one of the frequently seen complications of HSCT. However, hyperthyroidism due to Graves’ disease, autoimmune thyroiditis, and thyrotoxicosis are rare. Herein, we report a series of 4 patients who were euthyroid before HSCT but developed hyperthyroidism (3 of them developed autoimmune thyroid disease) after transplantation. PMID:26777050

  15. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation.

    PubMed

    Gilis, L; Morisset, S; Billaud, G; Ducastelle-Leprêtre, S; Labussière-Wallet, H; Nicolini, F-E; Barraco, F; Detrait, M; Thomas, X; Tedone, N; Sobh, M; Chidiac, C; Ferry, T; Salles, G; Michallet, M; Ader, F

    2014-05-01

    BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \\[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.

  16. A 54-Year-Old Woman with Donor Cell Origin of Multiple Myeloma after Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of CML

    PubMed Central

    Maestas, Erika; Jain, Shikha; Stiff, Patrick

    2016-01-01

    Chronic myeloid leukemia is a myeloproliferative disorder that may be treated with hematopoietic stem cell transplantation (HSCT). While posttransplantation relapse of disease resulting from a failure to eradicate the patient's original leukemia could occur, patients may also rarely develop a secondary malignancy or myelodysplastic syndrome (MDS) of donor origin termed donor cell leukemia (DCL). Cases of donor-derived acute myeloid leukemia (AML) or MDS after HSCT or solid tumor transplantation have been published. However, very few cases of donor-derived multiple myeloma (MM) exist. We describe a patient who developed a donor-derived MM following allogeneic HSCT from a sibling donor. PMID:26989529

  17. Longitudinal Changes in Body Mass and Composition in Survivors of Childhood Hematologic Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation

    PubMed Central

    Inaba, Hiroto; Yang, Jie; Kaste, Sue C.; Hartford, Christine M.; Motosue, Megan S.; Chemaitilly, Wassim; Triplett, Brandon M.; Shook, David R.; Pui, Ching-Hon; Leung, Wing

    2012-01-01

    Purpose To measure longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation (HSCT). Patients and Methods Body mass index (BMI) was analyzed in 179 survivors by category (underweight, healthy-weight, overweight, and obese) and by z score. Fat and lean body mass measured by dual-energy x-ray absorptiometry was analyzed as z scores. Results Over a median 6.6 years of follow-up, BMI z scores diminished significantly (0.32 pre-HSCT v −0.60 at 10 years post-HSCT; P < .001). Mean z scores for fat mass stayed within population norms, but those for lean mass remained below normal levels and diminished significantly over time (P = .018). Pre-HSCT BMI category and/or z score were strongly predictive of post-HSCT BMI (P < .001) and of fat and lean mass z scores (both P < .001). Survivors with extensive chronic graft-versus-host disease were more likely than others to have low BMI (P = .004) and low lean mass (P < .001) post-HSCT. Older age at HSCT (P = .015) and T-cell–depleted graft (P = .018) were predictive of lower post-HSCT BMI. Female patients had higher body fat (P = .002) and lower lean mass (P = .013) z scores than male patients, and black patients had higher fat mass z scores than white patients (P = .026). Conclusion BMI declines significantly after allogeneic HSCT for childhood hematologic malignancies, reflecting primarily a substantial decrease in lean mass but not fat mass. Monitoring and preservation of BMI and lean mass are vital, especially in those with the identified risk factors. PMID:23032628

  18. Human Biomarker Discovery and Predictive Models for Disease Progression for Idiopathic Pneumonia Syndrome Following Allogeneic Stem Cell Transplantation*

    PubMed Central

    Schlatzer, Daniela M.; Dazard, Jean-Eudes; Ewing, Rob M.; Ilchenko, Serguei; Tomcheko, Sara E.; Eid, Saada; Ho, Vincent; Yanik, Greg; Chance, Mark R.; Cooke, Kenneth R.

    2012-01-01

    Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy. PMID:22337588

  19. Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective

    PubMed Central

    Villasboas, Jose Caetano; Ansell, Stephen M.; Witzig, Thomas E.

    2016-01-01

    Patients with classic Hodgkin lymphoma (cHL) that has relapsed after autologous or allogeneic transplant have limited treatment options and a poor prognosis. Immunotherapy with agents that target the PROGRAMMED DEATH 1 (PD-1) receptor have demonstrated clinical activity with durable responses in early-phase clinical trials in this patient population; however, patients with a history of allogeneic stem cell transplantation (SCT) were intentionally excluded from participation in those studies due to concerns for reactivation of graft-versus-host disease (GVHD). We describe the clinical course of two patients with advanced cHL and prior treatment with allogeneic stem cell transplantation (SCT) that were treated with the PD-1 inhibitor pembrolizumab. Both patients had no active graft-versus-host disease (GVHD) at the time initiation of therapy and were maintained on low-dose prednisone. Treatment with pembrolizumab was well tolerated and not associated with reactivation of GVHD. Both patients responded (1 partial, 1 complete) and remain on therapy as of November 30, 2015. This report indicates that immunotherapy targeting the PD-1 pathway can be safely administered to patients with cHL and a history of allogeneic SCT and produce tumor responses. Further studies in this patient population are needed. PMID:26848626

  20. [Successful treatment of an overwhelming infection with granulocyte transfusion in severe aplastic anemia patient undergoing allogeneic peripheral blood stem cell transplantation].

    PubMed

    Kazuma, Yasuhiro; Ono, Yuichiro; Yonetani, Noboru; Imai, Yukihiro; Kawakami, Manabu; Hashimoto, Hisako; Ishikawa, Takayuki

    2016-04-01

    A 19-year-old woman complaining of fever and a sore throat was diagnosed with very severe aplastic anemia (AA) by bone marrow examination at a local hospital. Despite administration of antibiotics and granulocyte-colony stimulating factor to treat the soft tissue infection in her neck, her neutrophil count showed no increase. Because emergent allogeneic stem cell transplantation (SCT) was necessary, she was referred to our hospital. On admission, computed tomography revealed right-sided severe pharyngitis and lymphadenitis causing tracheal stenosis, and emergent intubation was required the next day. Granulocyte transfusion therapy (GTX) from related donors coupled with broad-spectrum antibiotic administration controlled the otherwise overwhelming infection. The patient received allogeneic peripheral blood SCT using a reduced-intensity conditioning regimen. After allogeneic SCT, successful engraftment was obtained. She was discharged from the hospital 59 days after allogeneic SCT. She remains alive and well, as of the latest follow up. This case clearly demonstrates that GTX is useful for controlling severe infection and enables patients with severe AA to receive allogeneic SCT safely. PMID:27169447

  1. Polyclonal anti-T-cell globulin as part of the preparative regimen for pediatric allogeneic stem-cell transplantation.

    PubMed

    Remberger, M; Mattsson, J; Ringdén, O

    2001-08-01

    To prevent graft rejection and graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation (ASCT), 56 children were given polyclonal anti-T-cell globulin (ATG) as part of the conditioning regimen. Of the 56 children in the cohort, 27 had a non-malignant disease and 29 had different hematological malignancies. Eight were in first remission of leukemia and the remainder in later stages. Donors were in 16 cases a human leucocyte antigen (HLA)-identical sibling and in 40 a matched unrelated donor (MUD). The control group comprised 16 patients with an HLA-identical donor; the children in this group were not treated with ATG. Side-effects related to the ATG treatment occurred in 63% of the patients and included fever, chills, headache, dyspnoea, nausea/vomiting, body pain, fall in blood pressure, and transient respiratory arrest. Engraftment occurred in 55 (98%) of the ATG-treated patients at a median of 17 (11-27) days after ASCT. One rejection occurred at 23 days post-SCT. The probabilities of acute graft-versus-host disease (GvHD) of grades II-IV were 6% for patients with an HLA-identical donor, 12% for controls, and 26% for the MUD group. Chronic GvHD occured in 20%, 50%, and 50% of patients in the three groups, respectively. Transplant-related mortality rates at 100 days were 6%, 6%, and 7%, respectively. The 5-yr survival rate was 94% and 81% using sibling donors, with and without ATG respectively, and 53% using unrelated donors (p = 0.002). Disregarding donor type, among the ATG-treated patients 5-yr survival rates were 46% in patients with a malignant disease and 77% in non-malignant disorders. Relapse and relapse-free survival rates were 42% and 46%, respectively. Five out of 12 patients who showed an early full donor chimerism in the T-cell lineage developed acute GvHD of grades II-IV, compared to none out of 13 patients being mixed chimeras (p = 0.01). Hence, the use of polyclonal ATG as part of conditioning prior to ASCT in children is safe

  2. Effects of Allogeneic Hematopoietic Stem Cell Transplantation Plus Thymus Transplantation on Malignant Tumors: Comparison Between Fetal, Newborn, and Adult Mice

    PubMed Central

    Zhang, Yuming; Hosaka, Naoki; Cui, Yunze; Shi, Ming

    2011-01-01

    We have recently shown that allogeneic intrabone marrow–bone marrow transplantation + adult thymus transplantation (TT) is effective for hosts with malignant tumors. However, since thymic and hematopoietic cell functions differ with age, the most effective age for such intervention needed to be determined. We performed hematopoietic stem cell transplantation (HSCT) using the intrabone marrow method with or without TT from fetal, newborn, and adult B6 mice (H-2b) into BALB/c mice (H-2d) bearing Meth-A sarcoma (H-2d). The mice treated with all types of HSCT + TT showed more pronounced regression and longer survival than those treated with HSCT alone in all age groups. Those treated with HSCT + TT showed increased numbers of CD4+ and CD8+ T cells but decreased numbers of Gr-1/Mac-1 myeloid suppressor cells and decreased percentages of FoxP3 cells in CD4+ T cells, compared with those treated with HSCT alone. In all mice, those treated with fetal liver cell (as fetal HSCs) transplantation + fetal TT or with newborn liver cell (as newborn HSCs) transplantation (NLT) + newborn TT (NTT) showed the most regression, and the latter showed the longest survival. The number of Gr-1/Mac-1 cells was the lowest, whereas the percentage of CD62L−CD44+ effector memory T cells and the production of interferon γ (IFN-γ) were highest in the mice treated with NLT + NTT. These findings indicate that, at any age, HSCT + TT is more effective against cancer than HSCT alone and that NLT + NTT is most effective. PMID:20672991

  3. Bone marrow mesenchymal stem cells suppressing activation of allogeneic cytokine-induced killer/natural killer cells either by direct or indirect interaction.

    PubMed

    Li, Yang; Qu, Yu H; Wu, Yan F; Liu, Ling; Lin, Xiang H; Huang, Ke; Wei, Jing

    2015-04-01

    Bone marrow mesenchymal stem cells (MSC) were recently found to be associated with some special immunological characteristics, the immunoregulatory effect of MSC was dose-dependent. Low amount of MSC was associated with mild immunosuppression or even immune activation, while the high amount of that was associated with significant immunosuppressive effect. In this study, by using a transwell system, we explored the effect of MSC on the cell cycle, apoptosis rate and the expression of CD69, an activation marker, on the allogeneic cord blood derived cytokine-induced killer(CIK)/natural killer(NK) cells. The results showed that either by transwell or mixed cell-cell co-culture, the MSC can effect CIK/NK cells on the cell cycle, such as arrested in the G0/G1 phase, diminished the ratio of cells in S, G2/M phase, and increased the apoptosis of them. MSC can also depress the expression of CD69 on these killer cells, as well as increased the ratio of CD4(+) CD25(+) CD127(low) T regulatory (Treg) cells in the CIK/NK cell culture system. We draw conclusions that either by transwell or mixed co-culture, the MSC can suppress activation of allogeneic CB-CIK/NK cells in a dose-dependent manner.

  4. Adoptable strategic approaches to improve outcomes of allogeneic peripheral blood stem cell transplantations from unrelated donors.

    PubMed

    Sohn, Sang Kyun; Moon, Joon Ho

    2014-06-01

    While previous studies have shown comparable clinical results for related and unrelated bone marrow transplantation (BMT), the transplantation outcomes for related and unrelated peripheral blood stem cell transplantation (PBSCT) may not follow the same pattern due to a higher incidence of graft-versus-host disease (GVHD)-related morbidity and mortality in the case of long-term survival after unrelated PBSCT. Thus, given the higher possibility of an impaired quality of life due to severe GVHD in long-term survivors who receive unrelated PBSCT, the selection of the stem cell source needs to be decided very carefully. In addition, strategic approaches, such as the extended use of immunosuppressant as a GVHD prophylaxis, the use of antithymocyte globulins (ATGs), choosing a younger donor, and optimizing the CD34+ cell dose, need to be adopted to improve the transplantation outcomes by minimizing GVHD-related morbidity and mortality in an unrelated PBSCT setting. This review article provides a comparison of BMT and PBSCT, and related and unrelated PBSCT, plus introduces several adoptable strategies to improve the outcomes of unrelated PBSCT.

  5. NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Porter, David L.; Alyea, Edwin P.; Antin, Joseph H.; DeLima, Marcos; Estey, Eli; Falkenburg, J.H. Frederik; Hardy, Nancy; Kroeger, Nicolaus; Leis, Jose; Levine, John; Maloney, David G.; Peggs, Karl; Rowe, Jacob M.; Wayne, Alan S.; Giralt, Sergio; Bishop, Michael R.; van Besien, Koen

    2010-01-01

    Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions (DLI) are commonly used for all diseases; although these interventions are remarkably effective for relapsed CML, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such there is an immediate need for well designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT. PMID:20699125

  6. Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: a prospective single centre study.

    PubMed

    Legrand, F; Grenouillet, F; Larosa, F; Dalle, F; Saas, P; Millon, L; Deconinck, E; Rohrlich, P S

    2011-06-01

    Digestive cryptosporidiosis (DC) can mimic GVHD after allogeneic haematopoietic stem cell transplantation (HSCT), thus requiring a reduction of immunosuppressive drugs and a specific therapy, whereas GVHD requires an intensification of immunosuppression. We systematically searched for cryptosporidiosis by light microscopy, immunochromatography and PCR in HSCT recipients who presented with at least one episode of diarrhoea. Of 115 consecutive patients allografted between July 2006 and November 2008, we analysed stools in 52 of 56 patients meeting these criteria. We identified Cryptosporidium parvum in 5 of the 52 patients (9.6%) at a median of 503 days (range 20-790) after HSCT. In those five patients, the median CD4+ cell and B lymphocyte counts were 60/mm3 (0-234) and 0/mm3 (0-96), respectively. Two patients died of invasive fungal infections. In the other three patients, diarrhoea disappeared after a median of 5 weeks following onset of bitherapy with azithromycine and nitazoxanide; they were still alive 433, 380 and 1179 days after the DC diagnosis. DC is probably under diagnosed after HSCT because it is difficult to detect during the asymptomatic phase. Early bitherapy and reduction of immunosuppression seem efficacious. In our series, DC has a seasonal pattern and is promoted by profound T lymphopenia.

  7. Varicella-zoster reactivation after allogeneic stem cell transplantation without routine prophylaxis--the incidence remains high.

    PubMed

    Blennow, Ola; Fjaertoft, Gustav; Winiarski, Jacek; Ljungman, Per; Mattsson, Jonas; Remberger, Mats

    2014-10-01

    One-year prophylaxis with acyclovir has been shown to effectively prevent varicella-zoster virus (VZV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) in a cohort that underwent transplantation in the beginning of the 2000s. Transplantation procedures have since changed considerably and reduced-intensity conditioning (RIC) is nowadays common. We investigated VZV reactivation without routine prophylaxis in a cohort of HSCT patients, 50% of whom had received RIC. The cumulative 2-year incidence of VZV reactivation was 20.7%. Risk factors in a multivariate analysis were treatment with mesenchymal stromal cells (relative hazard [RH], 1.65; confidence interval [CI], 1.07 to 2.54; P = .02), total body irradiation ≥6 Gy (RH, 1.55; CI, 1.14 to 2.13; P = .006), engraftment later than day 16 (RH, 1.46; CI, 1.07 to 2.00; P = .02), and age 0 to 19 years (RH, 1.68; CI, 1.21 to 2.35; P = .002). There was no difference in VZV reactivation between patients receiving myeloablative conditioning or RIC. VZV-related complications occurred in 29% of the patients with reactivation; most common were disseminated disease and postherpetic neuralgia. No single low-risk group for VZV reactivation could be identified. We conclude that VZV reactivation remains common after HSCT and carries a high complication rate, warranting prophylaxis.

  8. Risk Factors for Invasive Mold Infections and Implications for Choice of Prophylaxis after Allogeneic Stem Cell Transplantation.

    PubMed

    Blennow, Ola; Remberger, Mats; Törlén, Johan; Szakos, Attila; Ljungman, Per; Mattsson, Jonas

    2016-09-01

    Invasive mold infections (IMIs) are major complications after allogeneic hematopoietic stem cell transplantation (HSCT) with high mortality. We retrospectively investigated incidence and risk factors for IMI after 797 HSCTs in a center with high autopsy frequency, trying to identify patient groups that would potentially benefit from mold-active prophylaxis. The cumulative 1-year incidence of IMI was 2.1% in patients aged 21 to 40, 7.1% in patients aged 41 to 60, and 16.4% in patients > 60 years of age (P < .01 for patients aged 21 to 40 versus 41 to 60, P < .001 for patients aged 21 to 40 versus patients > 60). Risk factors for a new IMI in multivariate analysis were older age, grades II to IV acute graft-versus-host disease (GVHD) (risk hazard, 4.1; 95% CI, 1.9 to 8.8; P < .001), treatment with mesenchymal stromal cells (risk hazard, 4.0; 95% CI, 2.1 to 7.8; P < .001), transplantation with female donor to male recipient (risk hazard, 2.2; 95% CI, 1.1 to 4.3; P = .02), and hematopoietic stem cell transplantation-specific comorbidity index over 5 (risk hazard, 2.8; 95% CI, 1.1 to 6.8; P = .03). In patients with grade II acute GVHD, no IMI was seen after onset of acute GVHD in 109 HSCTs performed in patients < 40 years of age, as compared with 14 IMIs in 97 HSCTs (14%) performed in patients > 40 years of age (P < .001). To conclude, older age is an important risk factor for developing IMIs, and patients < 40 years of age with grade II acute GVHD do not appear to need mold-active prophylaxis unless receiving prolonged treatment with corticosteroids. PMID:27311967

  9. Risk Factors for Invasive Mold Infections and Implications for Choice of Prophylaxis after Allogeneic Stem Cell Transplantation.

    PubMed

    Blennow, Ola; Remberger, Mats; Törlén, Johan; Szakos, Attila; Ljungman, Per; Mattsson, Jonas

    2016-09-01

    Invasive mold infections (IMIs) are major complications after allogeneic hematopoietic stem cell transplantation (HSCT) with high mortality. We retrospectively investigated incidence and risk factors for IMI after 797 HSCTs in a center with high autopsy frequency, trying to identify patient groups that would potentially benefit from mold-active prophylaxis. The cumulative 1-year incidence of IMI was 2.1% in patients aged 21 to 40, 7.1% in patients aged 41 to 60, and 16.4% in patients > 60 years of age (P < .01 for patients aged 21 to 40 versus 41 to 60, P < .001 for patients aged 21 to 40 versus patients > 60). Risk factors for a new IMI in multivariate analysis were older age, grades II to IV acute graft-versus-host disease (GVHD) (risk hazard, 4.1; 95% CI, 1.9 to 8.8; P < .001), treatment with mesenchymal stromal cells (risk hazard, 4.0; 95% CI, 2.1 to 7.8; P < .001), transplantation with female donor to male recipient (risk hazard, 2.2; 95% CI, 1.1 to 4.3; P = .02), and hematopoietic stem cell transplantation-specific comorbidity index over 5 (risk hazard, 2.8; 95% CI, 1.1 to 6.8; P = .03). In patients with grade II acute GVHD, no IMI was seen after onset of acute GVHD in 109 HSCTs performed in patients < 40 years of age, as compared with 14 IMIs in 97 HSCTs (14%) performed in patients > 40 years of age (P < .001). To conclude, older age is an important risk factor for developing IMIs, and patients < 40 years of age with grade II acute GVHD do not appear to need mold-active prophylaxis unless receiving prolonged treatment with corticosteroids.

  10. T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Uzunel, Mehmet; Sairafi, Darius; Remberger, Mats; Mattsson, Jonas; Uhlin, Michael

    2014-07-15

    In this retrospective study, 209 patients with malignant disease were analyzed for levels of T-cell receptor excision circles (TRECs) for the first 24 months after allogeneic stem cell transplantation. CD3(+) cells were separated by direct antibody-coupled magnetic beads, followed by DNA extraction according to a standard protocol. The δRec-ψJα signal joint TREC was measured with real-time quantitative PCR. Patients were grouped based on malignant disease: chronic myeloid leukemia, chronic lymphatic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Patients were further subdivided based on TREC levels below (low-TREC) or above (high-TREC) median at each time point. TREC levels were then correlated to relapse incidence and relapse-free survival (RFS). For patients with AML, low TREC levels 2 months post-transplantation were correlated to high relapse incidence at 5 years (P<0.05). In patients with chronic leukemia, high TREC levels were correlated with improved RFS (P<0.05). For patients with MDS, high TREC levels at 9 months post-transplantation were associated with higher RFS at 5 years (P<0.02) and lower relapse incidence (P<0.02). This study shows the potential use of TREC measurement in blood to predict relapse in patients with AML and MDS after allogeneic hematopoietic stem cell transplantation. PMID:24617310

  11. Treatment of osteochondral defects in the rabbit's knee joint by implantation of allogeneic mesenchymal stem cells in fibrin clots.

    PubMed

    Berninger, Markus T; Wexel, Gabriele; Rummeny, Ernst J; Imhoff, Andreas B; Anton, Martina; Henning, Tobias D; Vogt, Stephan

    2013-01-01

    bone (11). The sandwich-technique combines bone grafting with current approaches in Tissue Engineering (5,6). This combination seems to be able to overcome the limitations seen in osteochondral grafts alone. After autologous bone grafting to the subchondral defect area, a membrane seeded with autologous chondrocytes is sutured above and facilitates to match the topology of the graft with the injured site. Of course, the previous bone reconstruction needs additional surgical time and often even an additional surgery. Moreover, to date, long-term data is missing (12). Tissue Engineering without additional bone grafting aims to restore the complex structure and properties of native articular cartilage by chondrogenic and osteogenic potential of the transplanted cells. However, again, it is usually only the cartilage tissue that is more or less regenerated. Additional osteochondral damage needs a specific further treatment. In order to achieve a regeneration of the multilayered structure of osteochondral defects, three-dimensional tissue engineered products seeded with autologous/allogeneic cells might provide a good regeneration capacity (11). Beside autologous chondrocytes, mesenchymal stem cells (MSC) seem to be an attractive alternative for the development of a full-thickness cartilage tissue. In numerous preclinical in vitro and in vivo studies, mesenchymal stem cells have displayed excellent tissue regeneration potential (13,14). The important advantage of mesenchymal stem cells especially for the treatment of osteochondral defects is that they have the capacity to differentiate in osteocytes as well as chondrocytes. Therefore, they potentially allow a multilayered regeneration of the defect. In recent years, several scaffolds with osteochondral regenerative potential have therefore been developed and evaluated with promising preliminary results (1,15-18). Furthermore, fibrin glue as a cell carrier became one of the preferred techniques in experimental cartilage

  12. Cross-talk between human neural stem/progenitor cells and peripheral blood mononuclear cells in an allogeneic co-culture model.

    PubMed

    Zhang, Hongxia; Shao, Bei; Zhuge, Qichuan; Wang, Peng; Zheng, Chengcai; Huang, Weilong; Yang, Chenqi; Wang, Brian; Su, Dong-Ming; Jin, Kunlin

    2015-01-01

    Transplantation of human neural stem/progenitor cells (hNSCs) as a regenerative cell replacement therapy holds great promise. However, the underlying mechanisms remain unclear. We, here, focused on the interaction between hNSCs and allogeneic peripheral blood mononuclear cells (PBMCs) in a co-culture model. We found that hNSCs significantly decrease the CD3+ and CD8+ T cells, reduce the gamma delta T cells and increase the regulatory T cells, along with reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines after co-culture. We also found that PBMCs, in turn, significantly promote the proliferation and differentiation of hNSCs. Our data suggest that hNSCs cross-talk with immune cells.

  13. Numerical impairment of nestin(+) bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML.

    PubMed

    Medinger, M; Krenger, W; Jakab, A; Halter, J; Buser, A; Bucher, C; Passweg, J; Tzankov, A

    2015-11-01

    The nestin(+) perivascular bone marrow (BM) stem cell niche (N(+)SCN) may be involved in GvHD. To investigate whether acute GvHD (aGvHD) reduces the number of N(+)SCN, we examined patients with AML who had undergone allogeneic hematopoietic stem cell transplantation. In the test cohort (n=8), the number of N(+)SCN per mm(2) in BM biopsies was significantly reduced in aGvHD patients at the time of aGvHD compared with patients who did not have aGvHD (1.2±0.78 versus 2.6±0.93, P=0.04). In the validation cohort (n=40), the number of N(+)SCN was reduced (1.9±0.99 versus 2.6±0.90 N(+)SCN/mm(2), P=0.05) in aGvHD patients. Receiver operating curves suggested that the cutoff score that best discriminated between patients with and without aGvHD was 2.29 N(+)SCN/mm(2). Applying this cutoff score, 9/11 patients with clinically relevant aGvHD (⩾grade 2) and 13/20 with any type of GvHD had decreased N(+)SCN numbers compared with only 10/29 patients without clinically relevant aGvHD (P=0.007) and 6/20 patients without any type of GvHD (P=0.028). In patients tracked over time, N(+)SCN density returned to normal after aGvHD resolved or remained stable in patients who did not have aGvHD. Our results show a decrease in the number of N(+)SCN in aGvHD.

  14. Beneficial treatment with risedronate in long-term survivors after allogeneic stem cell transplantation for hematological malignancies.

    PubMed

    Tauchmanovà, L; Selleri, C; Esposito, M; Di Somma, C; Orio, F; Bifulco, G; Palomba, S; Lombardi, G; Rotoli, B; Colao, A

    2003-12-01

    In this prospective randomized study we evaluated the effect of risedronate, an aminobisphosphonate, on bone mass and turnover in patients who had undergone allogeneic stem cell transplant (SCT) for hematological malignancies. Thirty-four patients (18 females, 16 males, age 32+/-10 years) with bone mineral density (BMD)

  15. A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

    PubMed

    Dyer, Gemma; Gilroy, Nicole; Bradford, Jennifer; Brice, Lisa; Kabir, Masura; Greenwood, Matt; Larsen, Stephen R; Moore, John; Hertzberg, Mark; Kwan, John; Brown, Louisa; Hogg, Megan; Huang, Gillian; Tan, Jeff; Ward, Christopher; Kerridge, Ian

    2016-02-01

    Four hundred and twenty-one adult allogeneic haematopoietic stem cell transplant (HSCT) survivors participated in a cross-sectional study to assess sexual dysfunction and infertility post-transplant. Survey instruments included the Sydney Post-Blood and Marrow Transplant (BMT) Survey, Functional Assessment of Cancer Treatment (FACT) - BMT, the Depression, Anxiety, Stress Scales (DASS 21), the Chronic Graft-versus-Host Disease (cGVHD) Activity Assessment- Patient Self Report (Form B), the Lee cGVHD Symptom Scale and The Post-Traumatic Growth Inventory. Most HSCT survivors reported sexual difficulties (51% of males; 66% of females). Men reported erectile dysfunction (79%) and decreased libido (61·6%) and women reported loss of libido (83%), painful intercourse (73%) and less enjoyment of sex (68%). Women also commonly reported vaginal dryness (73%), vaginal narrowing (34%) and vaginal irritation (26%). Woman had much higher rates of genital cGvHD than men (22% vs. 5%). Age and cGVHD were significantly associated with sexual dysfunction. Few survivors had children following transplant (3·3%). However, for those of reproductive age at HSCT, 22% reported trying to conceive, with 10·3% reporting success. This study is the largest to date exploring sexual function in survivors of allo-HSCT. This data provides the basis for health service reform to better meet the needs of HSCT survivors, including evidence to support counselling and education both pre- and post-transplant. PMID:26847746

  16. A randomized control trial of a psychosocial intervention for caregivers of allogeneic hematopoietic stem cell transplant patients: Effects on distress

    PubMed Central

    Laudenslager, Mark L.; Simoneau, Teri L.; Kilbourn, Kristin; Natvig, Crystal; Philips, Sam; Spradley, Janet; Benitez, Patrick; McSweeney, Peter; Mikulich-Gilbertson, Susan K.

    2015-01-01

    Caregivers of patients receiving allogeneic hematopoietic stem cell transplants (Allo-HSCT) serve a pivotal role in patient care but experience high stress, anxiety, and depression as a result. We theorized that a stress management adapted for Allo-HSCT caregivers would reduce distress compared to treatment as usual (TAU). From 267 consecutive caregivers of Allo-HSCT patients approached, 148 (mean=53.5 years, 75.7% female) were randomized to either psychosocial intervention (n=74) or TAU (n=74). Eight 1-on-1 stress management sessions delivered across the 100 day post-transplant period focused on understanding stress, changing role(s) as caregiver, cognitive behavioral stress management, pacing respiration, and identifying social support. Primary outcomes included perceived stress (psychological) and salivary cortisol awakening response (CAR) (physiological). Randomized groups were not statistically different at baseline. Mixed models analysis of covariance (intent-to-treat) showed that intervention was associated with significantly lower caregiver stress 3 months post-transplant (Mean=20.0, CI95=17.9-22.0) compared to TAU (Mean=23.0, CI95=21.0-25.0) with an effect size (ES) of 0.39 (p=0.039). Secondary psychological outcomes, including depression and anxiety, were significantly reduced with ESs of 0.46 and 0.66 respectively. Caregiver CAR did not differ from non-caregiving controls at baseline and was unchanged by intervention. Despite significant caregiving burden, this psychosocial intervention significantly mitigated distress in Allo-HSCT caregivers. PMID:25961767

  17. Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience.

    PubMed

    Strullu, Marion; Rialland, Fanny; Cahu, Xavier; Brissot, Eolia; Corradini, Nadege; Thomas, Caroline; Blin, Nicolas; Rialland, Xavier; Méchinaud, Françoise; Mohty, Mohamad

    2012-06-01

    This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.

  18. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

    PubMed

    Middeke, Jan M; Herold, Sylvia; Rücker-Braun, Elke; Berdel, Wolfgang E; Stelljes, Matthias; Kaufmann, Martin; Schäfer-Eckart, Kerstin; Baldus, Claudia D; Stuhlmann, Reingard; Ho, Anthony D; Einsele, Hermann; Rösler, Wolf; Serve, Hubert; Hänel, Mathias; Sohlbach, Kristina; Klesse, Christian; Mohr, Brigitte; Heidenreich, Falk; Stölzel, Friedrich; Röllig, Christoph; Platzbecker, Uwe; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian; Schetelig, Johannes

    2016-03-01

    Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

  19. Factors influencing the late phase of recovery after bone mineral density loss in allogeneic stem cell transplantation survivors.

    PubMed

    Anandi, P; Jain, N A; Tian, X; Wu, C O; Pophali, P A; Koklanaris, E; Ito, S; Savani, B N; Barrett, J; Battiwalla, M

    2016-08-01

    Accelerated bone mineral density loss (BMDL) occurs early after allogeneic stem cell transplantation (SCT) and is related to factors such as steroids and chronic GvHD. In order to understand the natural history of BMDL of SCT in the longer term, we evaluated a longitudinal cohort of 148 survivors with a median follow-up of 12 years (range 3-22 years). All women received hormone replacement therapy, and routine calcium/vitamin D supplementation was recommended but ∼50% of patients still had suboptimal vitamin D levels and bisphosphonates were rarely utilized. BMD significantly improved from 5 to 20+ years but the femoral neck and forearm remained vulnerable sites. Younger age, higher pretransplant body mass index (BMI) and increment in BMI post transplant were significantly associated with increased BMD and protected against osteopenia/osteoporosis. These findings support consideration of BMD loss in SCT survivors in two phases, an early phase of BMD loss (3-5 years) followed by a later phase of BMD recovery, with different protective and aggravating factors. Treatment- and transplant-related factors (such as steroids, immunosuppressives, chronic GvHD, vitamin D) are known to impact the early phase of BMD loss but age and BMI are more influential in the late phase of BMD recovery. PMID:27042843

  20. Pre-transplant weight loss predicts inferior outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndrome.

    PubMed

    Radujkovic, Aleksandar; Becker, Natalia; Benner, Axel; Penack, Olaf; Platzbecker, Uwe; Stölzel, Friedrich; Bornhäuser, Martin; Hegenbart, Ute; Ho, Anthony D; Dreger, Peter; Luft, Thomas

    2015-10-27

    Allogeneic stem cell transplantation (alloSCT) represents a curative therapeutic option for patients with myelodysplastic syndrome (MDS), but relapse and non-relapse mortality (NRM) limit treatment efficacy. Based on our previous observation in acute myeloid leukemia we investigated the impact of pre-transplant weight loss on post-transplant outcome in MDS patients. A total of 111 patients diagnosed with MDS according to WHO criteria transplanted between 2000 and 2012 in three different transplant centers were included into the analysis. Data on weight loss were collected from medical records prior to conditioning therapy and 3-6 months earlier. Patient, disease and transplant characteristics did not differ between patients with weight loss (2-5%, n = 17; > 5%, n = 17) and those without (n = 77). In a mixed effect model, weight loss was associated with higher risk MDS (p = 0.046). In multivariable analyses, pre-transplant weight loss exceeding 5% was associated with a higher incidence of relapse (p < 0.001) and NRM (p = 0.007). Pre-transplant weight loss of 2-5% and > 5% were independent predictors of worse disease-free (p = 0.023 and p < 0.001, respectively) and overall survival (p = 0.043 and p < 0.001, respectively). Our retrospective study suggests that MDS patients losing weight prior to alloSCT have an inferior outcome after transplantation. Prospective studies addressing pre-transplant nutritional interventions are highly warranted.

  1. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry.

    PubMed

    Gross, T G; Filipovich, A H; Conley, M E; Pracher, E; Schmiegelow, K; Verdirame, J D; Vowels, M; Williams, L L; Seemayer, T A

    1996-05-01

    Seven male patients in the David T Purtilo International X-linked Lymphoproliferative Disease (XLP) Registry have undergone allogeneic hematopoietic stem cell transplantation (HSCT). All patients received HSCT from HLA-identical donors: sibling BM, five; unrelated BM, one; and sibling umbilical cord blood, one. Ages at time of HSCT ranged from 5 to 30 years. Pre-HSCT clinical course varied, but four boys had a significant history of chronic and/or serious infections. Conditioning regimens varied: TBI containing regimens, four, chemotherapy only, three. All patients engrafted. Six developed grade I-II acute GVHD but no chronic GVHD. Four are alive and well with normal immune function greater than 3 years following HSCT. Three died within 100 days: disseminated adenovirus, one; polymicrobial sepsis, one; and multiple organ system failure and bleeding diathesis, one. No EBV-associated post-transplant complications were observed, even though all donors except the umbilical cord blood were EBV-seropositive. Unsuccessful HSCT was associated with age at HSCT (> 15 years), TBI-containing regimen and significant history for pre-HSCT infections. These results provide evidence that HSCT performed during childhood with HLA-identical sibling donors, regardless of EBV serostatus, offers the only curative therapy for XLP. PMID:8733691

  2. Glomerular diseases associated with chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: case reports.

    PubMed

    Chanswangphuwana, C; Townamchai, N; Intragumtornchai, T; Bunworasate, U

    2014-12-01

    Chronic graft-versus-host disease (cGVHD) is the major complication following allogeneic stem cell transplantation (allo-SCT). Nephrotic syndrome (NS) and other types of glomerulonephritis have been proposed to be the very rare forms of renal cGVHD. From 1991 to 2011, 253 patients underwent allo-SCT at our center. We report here 4 cases (1.6%) presenting with varieties of glomerular manifestations associated with cGVHD. The first case was typical NS. The renal pathology showed membranous nephropathy (MN). The second case was also MN, but this patient also had the pathology of focal segmental glomerulosclrosis (FSGS) and acute tubular necrosis (ATN). The third case showed lupus nephritis-like glomerular lesions with a high anti-nuclear antibody (ANA) titer. The fourth case presented with rapidly progressive glomerulonephritis (RPGN)-like symptoms. The kidney histology in this case was not available. The patient responded well to immunosuppressive therapy, but NS later recurred. Therefore, overt glomerular diseases after allo-SCT in Thai patients are not very rare. Monitoring urinalysis during withdrawal of immunosuppressive drugs and also during follow-up of patients with cGVHD may be considered.

  3. Pre-transplant weight loss predicts inferior outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndrome

    PubMed Central

    Radujkovic, Aleksandar; Becker, Natalia; Benner, Axel; Penack, Olaf; Platzbecker, Uwe; Stölzel, Friedrich; Bornhäuser, Martin; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter; Luft, Thomas

    2015-01-01

    Allogeneic stem cell transplantation (alloSCT) represents a curative therapeutic option for patients with myelodysplastic syndrome (MDS), but relapse and non-relapse mortality (NRM) limit treatment efficacy. Based on our previous observation in acute myeloid leukemia we investigated the impact of pre-transplant weight loss on post-transplant outcome in MDS patients. A total of 111 patients diagnosed with MDS according to WHO criteria transplanted between 2000 and 2012 in three different transplant centers were included into the analysis. Data on weight loss were collected from medical records prior to conditioning therapy and 3–6 months earlier. Patient, disease and transplant characteristics did not differ between patients with weight loss (2–5%, n = 17; > 5%, n = 17) and those without (n = 77). In a mixed effect model, weight loss was associated with higher risk MDS (p = 0.046). In multivariable analyses, pre-transplant weight loss exceeding 5% was associated with a higher incidence of relapse (p < 0.001) and NRM (p = 0.007). Pre-transplant weight loss of 2–5% and > 5% were independent predictors of worse disease-free (p = 0.023 and p < 0.001, respectively) and overall survival (p = 0.043 and p < 0.001, respectively). Our retrospective study suggests that MDS patients losing weight prior to alloSCT have an inferior outcome after transplantation. Prospective studies addressing pre-transplant nutritional interventions are highly warranted. PMID:26360778

  4. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass.

  5. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

  6. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Facenda-Lorenzo, María; Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J; Llanos-Gómez, Juan M; Cabello-Rodríguez, Ana I; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called "sanctuaries," are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

  7. Fatal human metapneumovirus and influenza B virus coinfection in an allogeneic hematopoietic stem cell transplant recipient.

    PubMed

    Ghattas, C; Mossad, S B

    2012-10-01

    Human metapneumovirus (hMPV) infection can occur in all age groups with significant morbidity and mortality. Coinfection with influenza virus occurs mainly with influenza type A and all reported cases recovered completely. We report the case of a 61-year-old man who had hematopoietic stem cell transplant for myelodysplastic syndrome. He was admitted to hospital for septic shock and neutropenia, and blood culture was positive for Pseudomonas aeruginosa. He rapidly developed respiratory failure and required ventilator support. His respiratory culture grew P. aeruginosa and hMPV. His course was complicated by persistent shock requiring vasopressor support, and repeat nasopharyngeal swab was positive for influenza type B and hMPV. His condition rapidly deteriorated, his family elected comfort care, and the patient died shortly thereafter. Coinfection with hMPV and influenza virus type B may have a poor outcome and can be fatal, especially in immunocompromised patients. PMID:22823898

  8. Reduced intensity conditioning HLA identical sibling donor allogeneic stem cell transplantation for patients with follicular lymphoma: long-term follow-up from two prospective multicenter trials

    PubMed Central

    Piñana, José Luis; Martino, Rodrigo; Gayoso, Jorge; Sureda, Anna; de la Serna, Javier; Díez-Martín, Jose Luis; Vazquez, Lourdes; Arranz, Reyes; Tomás, José Francisco; Sampol, Antonia; Solano, Carlos; Delgado, Julio; Sierra, Jorge; Caballero, Dolores

    2010-01-01

    Background Allogeneic hematopoietic stem cell transplantation is an effective treatment for patients with poor risk lymphoma, at least in part because of the graft-versus-lymphoma effect. Over the past decade, reduced intensity conditioning regimens have been shown to offer results similar to those of conventional high-dose conditioning regimens but with lower toxicity early after transplantation, especially in patients with chemosensitive disease at transplant. Design and Methods The aim of this study was to analyze the long-term outcome of patients with follicular lymphoma who received an HLA identical sibling allogeneic stem cell transplant with a reduced intensity conditioning regimen within prospective trials. The prospective multicenter studies considered included 37 patients with follicular lymphoma who underwent allogeneic stem cell transplantation between 1998 and 2007 with a fludarabine plus melphalan-based reduced intensity conditioning regimen. Results The median age of the patients was 50 years (range, 34–62 years) and the median follow-up was 52 months (range, 0.6 to 113 months). Most patients (77%) had stage III-IV at diagnosis, and patients had received a median of three lines of therapy before the reduced intensity conditioning allogeneic stem cell transplantation. At the time of transplantation, 14 patients were in complete remission, 16 in partial remission and 7 had refractory or progressive disease after salvage chemotherapy. The 4-year overall survival rates for patients in complete remission, partial remission, or with refractory or progressive disease were 71%, 48% and 29%, respectively (P=0.09), whereas the 4-year cumulative incidences of non-relapse mortality were 26% (95% CI, 11–61), 33% (95% CI, 16–68) and 71% (95% CI, 44–100), respectively. The incidence of relapse for the whole group was only 8% (95% CI, 2–23). Conclusions We conclude that this strategy of reduced intensity conditioning allogeneic stem cell transplantation

  9. Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors

    PubMed Central

    Anur, Praveen; Friedman, Danielle N; Sklar, Charles; Oeffinger, Kevin; Castiel, Mercedes; Kearney, Julia; Singh, Bhuvanesh; Prockop, Susan E; Kernan, Nancy A; Scaradavou, Andromachi; Kobos, Rachel; Curran, Kevin; Ruggiero, Julianne; Zakak, Nicole; O’Reilly, Richard J; Boulad, Farid

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least one year post-HSCT. Patients underwent either a total body irradiation (TBI) (N=18) or busulfan (N=4) based cytoreduction followed by T-cell depleted transplants from alternative donors. Twenty patients were alive at time of study with a 5 and 10 year overall survival of 100% and 84% and no evidence of chronic GVHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, four (22%) developed hypothyroidism, seven (39%) had insulin resistance and five (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism, and gonadal dysfunction after Busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes. PMID:26999465

  10. Human Induced Pluripotent Stem Cells Are Targets for Allogeneic and Autologous Natural Killer (NK) Cells and Killing Is Partly Mediated by the Activating NK Receptor DNAM-1

    PubMed Central

    Monecke, Sebastian; Cyganek, Lukas; Elsner, Leslie; Hübscher, Daniela; Walter, Lutz; Streckfuss-Bömeke, Katrin; Guan, Kaomei; Dressel, Ralf

    2015-01-01

    Human induced pluripotent stem cells (hiPSCs) could be used to generate autologous cells for therapeutic purposes, which are expected to be tolerated by the recipient. However, iPSC-derived grafts are at risk of giving rise to teratomas in the host, if residuals of tumorigenic cells are not rejected by the recipient. We have analyzed the susceptibility of hiPSC lines to allogeneic and autologous natural killer (NK) cells. IL-2-activated, in contrast to resting NK cells killed hiPSC lines efficiently (P=1.69x10-39). Notably, the specific lysis of the individual hiPSC lines by IL-2-activated NK cells was significantly different (P=1.72x10-6) and ranged between 46 % and 64 % in 51Cr-release assays when compared to K562 cells. The hiPSC lines were killed by both allogeneic and autologous NK cells although autologous NK cells were less efficient (P=8.63x10-6). Killing was partly dependent on the activating NK receptor DNAM-1 (P=8.22x10-7). The DNAM-1 ligands CD112 and CD155 as well as the NKG2D ligands MICA and MICB were expressed on the hiPSC lines. Low amounts of human leukocyte antigen (HLA) class I proteins, which serve as ligands for inhibitory and activating NK receptors were also detected. Thus, the susceptibility to NK cell killing appears to constitute a common feature of hiPSCs. Therefore, NK cells might reduce the risk of teratoma formation even after autologous transplantations of pluripotent stem cell-derived grafts that contain traces of pluripotent cells. PMID:25950680

  11. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome

    PubMed Central

    Robinson, Stephen P.; Sureda, Anna; Canals, Carmen; Russell, Nigel; Caballero, Dolores; Bacigalupo, Andrea; Iriondo, Arturo; Cook, Gordon; Pettitt, Andrew; Socie, Gerard; Bonifazi, Francesca; Bosi, Alberto; Michallet, Mauricette; Liakopoulou, Effie; Maertens, Johan; Passweg, Jakob; Clarke, Fiona; Martino, Rodrigo; Schmitz, Norbert

    2009-01-01

    Background The role of reduced intensity conditioning allogeneic stem transplantation (RICalloSCT) in the management of patients with Hodgkin’s lymphoma remains controversial. Design and Methods To further define its role we have conducted a retrospective analysis of 285 patients with HL who underwent a RICalloSCT in order to identify prognostic factors that predict outcome. Eighty percent of patients had undergone a prior autologous stem cell transplantation and 25% had refractory disease at transplant. Results Non-relapse mortality was associated with chemorefractory disease, poor performance status, age >45 and transplantation before 2002. For patients with no risk factors the 3-year non-relapse mortality rate was 12.5% compared to 46.2% for patients with 2 or more risk factors. The use of an unrelated donor had no adverse effect on the non-relapse mortality. Acute graft versus host disease (aGVHD) grades II–IV developed in 30% and chronic GVHD in 42%. The development of cGVHD was associated with a lower relapse rate. The disease progression rate at one and five years was 41% and 58.7% respectively and was associated with chemorefractory disease and extent of prior therapy. Donor lymphocyte infusions were administered to 64 patients for active disease of whom 32% showed a clinical response. Eight out of 18 patients receiving donor lymphocyte infusions alone had clinical responses. Progression-free and overall survival were both associated with performance status and disease status at transplant. Patients with neither risk factor had a 3-year PFS and overall survival of 42% and 56% respectively compared to 8% and 25% for patients with one or more risk factors. Relapse within six months of a prior autologous transplant was associated with a higher relapse rate and a lower progression-free. Conclusions This analysis identifies important clinical parameters that may be useful in predicting the outcome of RICaIICalloSCT in Hodgkin’s lymphoma. PMID:19066328

  12. NCI First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biology Underlying Recurrence of Malignant Disease following Allogeneic HSCT: Graft-versus-Tumor/Leukemia Reaction.

    PubMed

    Miller, Jeffrey S; Warren, Edus H; van den Brink, Marcel R M; Ritz, Jerome; Shlomchik, Warren D; Murphy, William J; Barrett, A John; Kolb, Hans Jochem; Giralt, Sergio; Bishop, Michael R; Blazar, Bruce R; Falkenburg, J H Frederik

    2010-05-01

    The success of allogeneic hematopoietic stem cell transplantation (HSCT) depends on the infusion of benign stem cells as well as lymphocytes capable of participating in a graft-versus-tumor/leukemia (GVL) reaction. Clinical proof of concept is derived from studies showing increased relapse after the infusion of lymphocyte depleted hematopoietic grafts as well as the therapeutic efficacy of donor lymphocyte infusions without chemotherapy to treat relapse in some diseases. Despite this knowledge, relapse after allogeneic HSCT is common with rates approaching 40% in those with high-risk disease. In this review, we cover the basic biology and potential application to exploit adaptive T cell responses, minor histocompatibility antigens, contraction and suppression mechanisms that hinder immune responses, adaptive B cell responses and innate NK cell responses, all orchestrated in a GVL reaction. Optimal strategies to precisely balance immune responses to favor GVL without harmful graft-versus-host disease (GVHD) are needed to protect against relapse, treat persistent disease and improve disease-free survival after HSCT.

  13. Everolimus in combination with cyclosporin a as pre- and posttransplantation immunosuppressive therapy in nonmyeloablative allogeneic hematopoietic stem cell transplantation.

    PubMed

    Junghanss, Christian; Rathsack, Susanne; Wacke, Rainer; Weirich, Volker; Vogel, Heike; Drewelow, Bernd; Mueller, Sabrina; Altmann, Simone; Freund, Mathias; Lange, Sandra

    2012-07-01

    Everolimus (RAD001) is an mTOR inhibitor that has been successfully used as an immunosuppressant in solid-organ transplantation. Data in allogeneic hematopoietic stem cell transplantation (HSCT) is limited. This study aimed to investigate pharmacokinetics, safety, and efficacy of RAD001 in a canine allogeneic HSCT model. First, pharmacokinetics of RAD001 were performed in healthy dogs in order to determine the appropriate dosing. Doses of 0.25 mg RAD001 twice daily in combination with 15 mg/kg cyclosporin A (CsA) twice daily were identified as appropriate starting doses to achieve the targeted range of RAD001 (3-8 μg/L) when orally administered. Subsequently, 10 dogs were transplanted using 2 Gy total body irradiation (TBI) for conditioning and 0.25 mg RAD001 twice daily plus 15 mg/kg CsA twice daily for pre- and posttransplantation immunosuppression. Seven of the 10 transplanted dogs were maintained at the starting RAD001 dose throughout the study. For the remaining 3 dogs, dose adjustments were necessary. RAD001 accumulation over time did not occur. All dogs initially engrafted. Five dogs eventually rejected the graft (weeks 10, 10, 13, 27, and 56). Two dogs died of pneumonia (weeks 8 and 72) but were chimeric until then. Total cholesterol rose from median 4.1 mmol/L (3.5-5.7 mmol/L) before HSCT to 6.0 mmol/l (5.0-8.5 mmol/l) at day 21 after HSCT, but remained always within normal range. Changes in creatinine and triglyceride values were not observed. Long-term engraftment rates were inferior to sirolimus/CsA and mycophenolate mofetil (MMF)/CsA regimen, respectively. RAD001/CsA caused a more pronounced reduction of platelet counts to median 2 × 10(9)/L (range: 0-21 × 10(9)/L) and longer time to platelet recovery of 21 days (range: 14-24 days) compared with MMF/CsA. CsA c(2h) levels were significantly enhanced in the RAD001/CsA regimen, but c(0h) and area under the curve from 0 to 12 hours (AUC(0-12h)) values did not differ compared with an MMF

  14. CD34+ Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation for Non-Malignant Disease

    ClinicalTrials.gov

    2016-03-10

    Bone Marrow Failure Syndrome; Severe Aplastic Anemia; Severe Congenital Neutropenia; Amegakaryocytic Thrombocytopenia; Diamond-Blackfan Anemia; Schwachman Diamond Syndrome; Primary Immunodeficiency Syndromes; Acquired Immunodeficiency Syndromes; Histiocytic Syndrome; Familial Hemophagocytic Lymphocytosis; Lymphohistiocytosis; Macrophage Activation Syndrome; Langerhans Cell Histiocytosis (LCH); Hemoglobinopathies; Sickle Cell Disease; Sickle Cell-beta-thalassemia

  15. Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Nie, Di-min; Wu, Qiu-ling; Zhu, Xia-xia; Zhang, Ran; Zheng, Peng; Fang, Jun; You, Yong; Zhong, Zhao-dong; Xia, Ling-hui; Hong, Mei

    2015-10-01

    Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-β in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-β promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD. PMID:26489624

  16. Neurological complications after allogeneic hematopoietic stem cell transplantation in children, a single center experience.

    PubMed

    Azik, Fatih; Yazal Erdem, Arzu; Tavil, Betül; Bayram, Cengiz; Tunç, Bahattin; Uçkan, Duygu

    2014-06-01

    In this study, we retrospectively examined the data of children who underwent allo-HSCT from HLA-matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow-up of neurologic complications. BU-based conditioning regimens were used in most of the cases (n = 62). The median duration of follow-up for the 89 patients was 20 months (range 1-41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range -6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3-17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%).

  17. Changes in serum uric acid levels after allogeneic hematologic stem cell transplantation: A retrospective cohort study

    PubMed Central

    Joo, Sang Hyun; Park, Jin Kyun; Lee, Eunyoung Emily; Song, Yeong Wook

    2016-01-01

    Background Since cell turnover in the hematopoietic system constitutes a major source of uric acid (UA) production, we investigated whether hematopoietic stem cell transplantation (HSCT) is associated with significant changes in serum UA levels in patients with hematological disorders. Methods Patients who underwent HSCT at our institution between 2001 and 2012 were retrospectively enrolled. Serum UA levels at 3 months before, 1 week before, and 3 months and 1 year after HSCT were examined. Results Complete clinical and laboratory information including data regarding UA levels was available for 93 patients. At baseline, the mean UA level was 4.9±2.1 mg/dL, with an overall prevalence of hyperuricemia of 15% (defined as serum UA>6.8 mg/dL). Mean UA levels tended to be higher in patients with acute myeloid leukemia (4.8±2.0 mg/dL) and non-Hodgkin lymphoma (5.1±2.3 mg/dL) and lower in patients with aplastic anemia (mean, 4.2±1.8 mg/dL). UA levels dropped during myeloablative conditioning, reaching a nadir on the day of HSCT (3.27±1.4 mg/dL). Over the 3 months following HSCT, UA levels rose sharply (5.0±2.1 mg/dL) and remained stable up to 1 year after HSCT (5.5±1.6 mg/dL). UA levels in HSCT recipients at 12 months correlated with those of their respective graft donors (Pearson r=0.406, P=0.001). Conclusion HSCT is associated with significant changes in uric acid levels in patients with hematologic disorders. PMID:27722132

  18. Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma.

    PubMed

    Anderlini, Paolo; Saliba, Rima M; Ledesma, Celina; Plair, Tamera; Alousi, Amin M; Hosing, Chitra M; Khouri, Issa F; Nieto, Yago; Popat, Uday R; Shpall, Elizabeth J; Fanale, Michelle A; Hagemeister, Frederick B; Oki, Yasuhiro; Neelapu, Saatva; Romaguera, Jorge E; Younes, Anas; Champlin, Richard E

    2016-07-01

    Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine-fludarabine-melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine-fludarabine-melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.

  19. A Prospective, Randomized, Masked, and Placebo-Controlled Efficacy Study of Intraarticular Allogeneic Adipose Stem Cells for the Treatment of Osteoarthritis in Dogs

    PubMed Central

    Harman, Robert; Carlson, Kim; Gaynor, Jamie; Gustafson, Scott; Dhupa, Sarit; Clement, Keith; Hoelzler, Michael; McCarthy, Tim; Schwartz, Pamela; Adams, Cheryl

    2016-01-01

    Osteoarthritis (OA) is a degenerative joint disease with a high prevalence in dogs. Mesenchymal stem cells (MSCs) have been used to treat humans, dogs, and horses with OA. This report describes a prospective, randomized, blinded, and placebo-controlled clinical efficacy study of intraarticular allogeneic adipose stem cells for the treatment of dogs with OA. Health assessments and measurements of pain and activity impairment were performed at baseline and at selected time points through day 60. The primary outcome variable was the owner Client-Specific Outcome Measurement (CSOM) and secondary measures included veterinary pain on manipulation, veterinary global score, and owner global score. The dogs were treated with either a saline placebo or a single dose of allogeneic adipose-derived MSCs in either one or two joints. Seventy-four dogs were statistically analyzed for efficacy outcomes. Success in the primary outcome variable, CSOM, was statistically improved in the treated dogs compared to the placebo dogs (79.2 versus 55.4%, p = 0.029). The veterinary pain on manipulation score (92.8 versus 50.2%, p = 0.017) and the veterinary global score (86.9 versus 30.8%, p = 0.009) were both statistically improved in treated dogs compared to placebo. There was no detected significant difference between treated and placebo dogs in the incidence of adverse events or negative health findings. Allogeneic adipose-derived stem cell treatment was shown to be efficacious compared to placebo. This large study of dogs also provides valuable animal clinical safety and efficacy outcome data to our colleagues developing human stem cell therapy. PMID:27695698

  20. Mannose-binding lectin levels and major infections in a cohort of very long-term survivors after allogeneic stem cell transplantation

    PubMed Central

    Osthoff, Michael; Rovó, Alicia; Stern, Martin; Danner, Doris; Gratwohl, Alois; Tichelli, André; Trendelenburg, Marten

    2010-01-01

    Background Life-threatening infections are a major cause of death after allogeneic stem cell transplantation. Complement Mannose-binding lectin is a key component of innate immunity. Functional deficiency of mannose-binding lectin due to genetic polymorphism is frequent. Previous reports showed conflicting results with respect to the influence of functional mannose-binding lectin deficiency on infectious risk after allogeneic stem cell transplantation. The aim of this study was to clarify the impact of low mannose-binding lectin levels on infectious risk in a unique cohort of very long-term survivors after stem cell transplantation. Design and Methods Incidence of major infections was evaluable in 43 out of 44 very long-term survivors (over ten years) and studied retrospectively in relation to mannose-binding lectin serum concentrations. Results Recipients with mannose-binding lectin levels below 1,000 ng/mL were at increased risk to suffer from one or more major infections (P=0.002) during entire follow up. Infectious susceptibility was increased after neutrophil recovery, particularly until 24 months (Hazard Ratio 3.4) with sustained effects afterwards (Hazard Ratio 2.9). Mannose-binding lectin serum concentrations below 1,000 ng/mL were independently associated with major infections after neutrophil recovery (P=0.009). In subgroup analyses occurrence of severe herpes virus infections in particular was associated with significantly lower mannose-binding lectin levels (P=0.02). Conclusions Our findings indicate that low mannose-binding lectin levels may predict markedly increased susceptibility to severe infections with sustained effects even late after allogeneic stem cell transplantation. Determinations of mannose-binding lectin status should therefore be included into pre-transplantation risk assessment. PMID:20418242

  1. A Prospective, Randomized, Masked, and Placebo-Controlled Efficacy Study of Intraarticular Allogeneic Adipose Stem Cells for the Treatment of Osteoarthritis in Dogs

    PubMed Central

    Harman, Robert; Carlson, Kim; Gaynor, Jamie; Gustafson, Scott; Dhupa, Sarit; Clement, Keith; Hoelzler, Michael; McCarthy, Tim; Schwartz, Pamela; Adams, Cheryl

    2016-01-01

    Osteoarthritis (OA) is a degenerative joint disease with a high prevalence in dogs. Mesenchymal stem cells (MSCs) have been used to treat humans, dogs, and horses with OA. This report describes a prospective, randomized, blinded, and placebo-controlled clinical efficacy study of intraarticular allogeneic adipose stem cells for the treatment of dogs with OA. Health assessments and measurements of pain and activity impairment were performed at baseline and at selected time points through day 60. The primary outcome variable was the owner Client-Specific Outcome Measurement (CSOM) and secondary measures included veterinary pain on manipulation, veterinary global score, and owner global score. The dogs were treated with either a saline placebo or a single dose of allogeneic adipose-derived MSCs in either one or two joints. Seventy-four dogs were statistically analyzed for efficacy outcomes. Success in the primary outcome variable, CSOM, was statistically improved in the treated dogs compared to the placebo dogs (79.2 versus 55.4%, p = 0.029). The veterinary pain on manipulation score (92.8 versus 50.2%, p = 0.017) and the veterinary global score (86.9 versus 30.8%, p = 0.009) were both statistically improved in treated dogs compared to placebo. There was no detected significant difference between treated and placebo dogs in the incidence of adverse events or negative health findings. Allogeneic adipose-derived stem cell treatment was shown to be efficacious compared to placebo. This large study of dogs also provides valuable animal clinical safety and efficacy outcome data to our colleagues developing human stem cell therapy.

  2. Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma.

    PubMed

    Anderlini, Paolo; Saliba, Rima M; Ledesma, Celina; Plair, Tamera; Alousi, Amin M; Hosing, Chitra M; Khouri, Issa F; Nieto, Yago; Popat, Uday R; Shpall, Elizabeth J; Fanale, Michelle A; Hagemeister, Frederick B; Oki, Yasuhiro; Neelapu, Saatva; Romaguera, Jorge E; Younes, Anas; Champlin, Richard E

    2016-07-01

    Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine-fludarabine-melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine-fludarabine-melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era. PMID:27064056

  3. Tendon Reattachment to Bone in an Ovine Tendon Defect Model of Retraction Using Allogenic and Xenogenic Demineralised Bone Matrix Incorporated with Mesenchymal Stem Cells

    PubMed Central

    2016-01-01

    Background Tendon-bone healing following rotator cuff repairs is mainly impaired by poor tissue quality. Demineralised bone matrix promotes healing of the tendon-bone interface but its role in the treatment of tendon tears with retraction has not been investigated. We hypothesized that cortical demineralised bone matrix used with minimally manipulated mesenchymal stem cells will result in improved function and restoration of the tendon-bone interface with no difference between xenogenic and allogenic scaffolds. Materials and Methods In an ovine model, the patellar tendon was detached from the tibial tuberosity and a complete distal tendon transverse defect measuring 1 cm was created. Suture anchors were used to reattach the tendon and xenogenic demineralised bone matrix + minimally manipulated mesenchymal stem cells (n = 5), or allogenic demineralised bone matrix + minimally manipulated mesenchymal stem cells (n = 5) were used to bridge the defect. Graft incorporation into the tendon and its effect on regeneration of the enthesis was assessed using histomorphometry. Force plate analysis was used to assess functional recovery. Results Compared to the xenograft, the allograft was associated with significantly higher functional weight bearing at 6 (P = 0.047), 9 (P = 0.028), and 12 weeks (P = 0.009). In the allogenic group this was accompanied by greater remodeling of the demineralised bone matrix into tendon-like tissue in the region of the defect (p = 0.015), and a more direct type of enthesis characterized by significantly more fibrocartilage (p = 0.039). No failures of tendon-bone healing were noted in either group. Conclusion Demineralised bone matrix used with minimally manipulated mesenchymal stem cells promotes healing of the tendon-bone interface in an ovine model of acute tendon retraction, with superior mechanical and histological results associated with use of an allograft. PMID:27606597

  4. Fate of bone marrow mesenchymal stem cells following the allogeneic transplantation of cartilaginous aggregates into osteochondral defects of rabbits.

    PubMed

    Yoshioka, Tomokazu; Mishima, Hajime; Kaul, Zeenia; Ohyabu, Yoshimi; Sakai, Shinsuke; Ochiai, Naoyuki; Kaul, Sunil C; Wadhwa, Renu; Uemura, Toshimasa

    2011-06-01

    The purpose of this study was to track mesenchymal stem cells (MSCs) labelled with internalizing quantum dots (i-QDs) in the reparative tissues, following the allogeneic transplantation of three-dimensional (3D) cartilaginous aggregates into the osteochondral defects of rabbits. QDs were conjugated with a unique internalizing antibody against a heat shock protein-70 (hsp70) family stress chaperone, mortalin, which is upregulated and expressed on the surface of dividing cells. The i-QDs were added to the culture medium for 24 h. Scaffold-free cartilaginous aggregates formed from i-QD-labelled MSCs (i-MSCs), using a 3D culture system with chondrogenic supplements for 1 week, were transplanted into osteochondral defects of rabbits. At 4, 8 and 26 weeks after the transplantation, the reparative tissues were evaluated macroscopically, histologically and fluoroscopically. At as early as 4 weeks, the defects were covered with a white tissue resembling articular cartilage. In histological appearance, the reparative tissues resembled hyaline cartilage on safranin-O staining throughout the 26 weeks. In the deeper portion, subchondral bone and bone marrow were well remodelled. On fluoroscopic evaluation, QDs were tracked mainly in bone marrow stromata, with some signals detected in cartilage and the subchondral bone layer. We showed that the labelling of rabbit MSCs with anti-mortalin antibody-conjugated i-QDs is a tolerable procedure and provides a stable fluorescence signal during the cartilage repair process for up to 26 weeks after transplantation. The results suggest that i-MSCs did not inhibit, and indeed contributed to, the regeneration of osteochondral defects.

  5. Allogeneic hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: potential benefit of medium-dose etoposide conditioning.

    PubMed

    Imamura, Masahiro; Shigematsu, Akio

    2015-01-01

    The outcomes of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) are unsatisfactory. Therefore, allogeneic (allo) HSCT has been applied to those patients in first complete remission (CR1), and has shown a long-term survival rate of approximately 50 %. In terms of myeloablative conditioning (MAC) regimen, higher dose of cyclophosphamide (CY) and total body irradiation (TBI) (the standard CY + TBI) has been generally applied to allo HSCT. Other MAC regimens such as busulfan-based or etoposide-based regimens have also been used. Among those, medium-dose etoposide (ETP) in addition to the standard CY + TBI conditioning regimen appears to be promising for allo HSCT in adult ALL when transplanted in ALL patients aged under 50 years in CR1 and also in CR2, showing an excellent outcome without increasing relapse or transplant-related mortality (TRM) rates. By contrast, reduced-intensity conditioning (RIC) regimens have also been applied to adult ALL patients and favorable outcomes have been obtained; however, relapse and TRM rates remain high. Therefore, an allo HSCT conditioning regimen which deserves further study for adult ALL patients aged under 50 years in CR1 and CR2 appears to be medium-dose ETP + CY + TBI and RIC is suitable for patients aged over 50 years or for younger patients with comorbid conditions. On the contrary, new therapeutic strategies for adult ALL patients are increasingly utilized with better outcomes; namely, various tyrosine kinase inhibitors for Philadelphia chromosome (Ph)-positive ALL, human leukocyte antigen-haploidentical HSCT, and pediatric-inspired regimens for Ph-negative ALL. Therefore, the optimal treatment modality should be selected considering patient's age, Ph-positivity, donor availability, risk classification, efficacy, and safety. PMID:26322249

  6. Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

    PubMed

    Pichler, Herbert; Fritsch, Gerhard; König, Margit; Daxberger, Helga; Glogova, Evgenia; Pötschger, Ulrike; Breuer, Sabine; Lawitschka, Anita; Güclü, Ece D; Karlhuber, Susanne; Holter, Wolfgang; Haas, Oskar A; Lion, Thomas; Matthes-Martin, Susanne

    2016-06-01

    The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.

  7. Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

    PubMed

    Pichler, Herbert; Fritsch, Gerhard; König, Margit; Daxberger, Helga; Glogova, Evgenia; Pötschger, Ulrike; Breuer, Sabine; Lawitschka, Anita; Güclü, Ece D; Karlhuber, Susanne; Holter, Wolfgang; Haas, Oskar A; Lion, Thomas; Matthes-Martin, Susanne

    2016-06-01

    The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse. PMID:26996395

  8. Ferritin as an early marker of graft rejection after allogeneic hematopoietic stem cell transplantation in pediatric patients.

    PubMed

    Döring, Michaela; Cabanillas Stanchi, Karin Melanie; Feucht, Judith; Queudeville, Manon; Teltschik, Heiko-Manuel; Lang, Peter; Feuchtinger, Tobias; Handgretinger, Rupert; Müller, Ingo

    2016-01-01

    Diagnosis of adverse events following hematopoietic stem cell transplantation (HSCT) is mainly assigned to clinical symptoms or biopsies and thus rather unspecific and/or invasive. Studies indicate a distinct role of serum ferritin in HSCT and its correlation with adverse events such as graft-versus-host disease (GvHD), veno-occlusive disease (VOD), or infections. However, published data on the relevance of ferritin as a prognostic marker for post-transplant adverse events is rare, especially in pediatric patients. The present study analyzes ferritin plasma concentrations of 138 pediatric patients after HSCT between 2007 and 2010 including the control group (n = 21). Given the initial results regarding ferritin as a significant predictor for acute graft rejection after allogeneic HSCT in 9 of the 138 pediatric patients, serum ferritin of all pediatric patients (n = 27) who experienced graft rejection between 2007 and 2014 was analyzed. In addition, laboratory parameters including C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, and D-dimer as possible differentiation markers for graft rejection were determined. In 24 (88.9 %) of the 27 pediatric patients with graft rejection, a significant increase of ferritin levels was observed 1 to 7 days prior to (P < 0.0001) and at the time of graft rejection (P < 0.0001). Moreover, there was an increase of D-dimer, CRP, LDH, and fibrinogen 1-7 days before graft rejection. Ferritin increased significantly at time of VOD (P = 0.0067), at time of intestinal (P < 0.0001) and skin GvHD (P < 0.0001), and at time of sepsis (P = 0.0005) and bacteremia (P = 0.0029). Ferritin might serve as a readily available identification marker for differentiation and identification of adverse events after HSCT in combination with other laboratory markers. PMID:26611853

  9. Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    PubMed Central

    Bueno, Nadjanara Dorna; Dulley, Frederico Luiz; Saboya, Rosaura; Amigo Filho, José Ulysses; Coracin, Fabio Luiz; Chamone, Dalton de Alencar Fischer

    2011-01-01

    Background Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. Objectives To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. Methods Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years). All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days) and 17 days (Range: 7 - 46 days) for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. Results The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001), as did grade II acute graft-versus-host disease (p-value = 0.0377) and mild chronic graft-versus-host disease (p-value < 0.0001). Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one) and infection (two). The cause of death could not be determined for two patients. Conclusion The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate. PMID:23049292

  10. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.

    PubMed

    Pusic, Iskra; Choi, Jaebok; Fiala, Mark A; Gao, Feng; Holt, Matthew; Cashen, Amanda F; Vij, Ravi; Abboud, Camille N; Stockerl-Goldstein, Keith E; Jacoby, Meghan A; Uy, Geoffrey L; Westervelt, Peter; DiPersio, John F

    2015-10-01

    Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the

  11. The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: Candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation.

    PubMed

    Mohamed, Yehia S; Bashawri, Layla A; Vatte, Chittibabu; Abu-Rish, Eman Y; Cyrus, Cyril; Khalaf, Wafaa S; Browning, Michael J

    2016-09-01

    Adoptive T-cell immunotherapy is a promising approach to manage and maintain relapse-free survival of leukemia patients, especially following allogeneic stem cell transplantation. Post-transplant adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) of the donor origin provide graft-versus-tumor effects, with or without graft-versus-host disease. Myeloid leukemias express immunogenic leukemia associated antigens (LAAs); such as WT-1, PRAME, MAGE, h-TERT and others, most of them are able to induce specific T cell responses whenever associated with the proper co-stimulation. We investigated the ability of a LAA-expressing hybridoma cell line to induce CTL clones in PBMCs of HLA-matched healthy donors in vitro. The CTL clones were induced by repetitive co-culture with LAAs-expressing, HLA-A*0201(+) hybrid cell line, generated by fusion of leukemia blasts to human immortalized APC (EBV-sensitized B-lymphoblastoid cell line; HMy2). The induced cytotoxic T cell clones were phenotypically and functionally characterized by pentamer analysis, IFN-γ release ELISPOT and cellular cytotoxicity assays. All T cell lines showed robust peptide recognition and functional activity when sensitized with HLA-A*0201-restricted WT-1235-243, hTERT615-624 or PRAME100-108 peptides-pulsed T2 cells, in addition to partially HLA-matched leukemia blasts. This study demonstrates the feasibility of developing multi-tumor antigen-specific T cell lines in allogeneic PBMCs in vitro, using LAA-expressing tumor/HMy2 hybrid cell line model, for potential use in leukemia adoptive immunotherapy in partially matched donor-recipient setting. PMID:27490939

  12. Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections

    PubMed Central

    Corre, Elise; Carmagnat, Maryvonnick; Busson, Marc; de Latour, Regis Peffault; Robin, Marie; Ribaud, Patricia; Toubert, Antoine; Rabian, Claire; Socié, Gerard

    2010-01-01

    Immune reconstitution was analyzed in 140 consecutive patients who were 2-year disease-free and who underwent myeloablative allogeneic transplantation. A CD4 and CD8 defect was observed involving naive, terminally differentiated, memory and competent cells and above limits values for activated subsets. Natural killer cells normalize at six months while we observed expansion of CD19+/CD5+ B cells after three months and a persisting defect of memory B cells. Chronic graft-versus-host disease did not influence significantly those parameters for CD8 subsets while the naïve and competent CD4 subsets were strongly affected. But the most profound impact of chronic graft-versus-host disease was on B-cell subsets, especially on the memory B population. The cumulative incidence of late severe infections was low (14% at four years). Using Cox’s models, only low B-cell counts at 12 (P=0.02) and 24 (P=0.001) months were associated with the hazard of developing late infection, in particular if patients did not develop chronic graft-versus-host disease. PMID:20133894

  13. Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation.

    PubMed

    Herbert, K E; Spencer, A; Grigg, A; Ryan, G; McCormack, C; Prince, H M

    2004-09-01

    Cutaneous T-cell lymphomas (CTCL) are rare diseases that, in their advanced stages or in transformation, have a poor prognosis. Autologous stem cell transplantation (Au-SCT) after high-dose therapy has yielded disappointing results. Allogeneic transplantation (allo-SCT) provides the potential advantage of an immune-mediated graft-versus-lymphoma (GVL) effect. Reduced-intensity allo-SCT potentially offers a GVL effect, but with diminished toxicity related to the induction regimen; however, published experience with this approach in CTCL is limited. We report a series of three patients (age 35-49) with advanced, refractory (n=2) or transformed (n=1) CTCL who underwent reduced-intensity allo-SCT in the context of active disease. All three survived the peri-transplant period and, despite later having disease relapse, all exhibited evidence of a GVL effect. Relapses of the disease were in the context of immune suppression for graft-versus-host disease (GVHD), and when immune suppression was reduced, responses were regained. A comparison is made of these results to those in a review of the published literature to date. We conclude that while a GVL can be achieved for CTCL with reduced-intensity allogeneic transplantation, the clinical benefits are short lived and novel approaches are required to obtain sustained remissions. PMID:15286686

  14. Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation.

    PubMed

    Herbert, K E; Spencer, A; Grigg, A; Ryan, G; McCormack, C; Prince, H M

    2004-09-01

    Cutaneous T-cell lymphomas (CTCL) are rare diseases that, in their advanced stages or in transformation, have a poor prognosis. Autologous stem cell transplantation (Au-SCT) after high-dose therapy has yielded disappointing results. Allogeneic transplantation (allo-SCT) provides the potential advantage of an immune-mediated graft-versus-lymphoma (GVL) effect. Reduced-intensity allo-SCT potentially offers a GVL effect, but with diminished toxicity related to the induction regimen; however, published experience with this approach in CTCL is limited. We report a series of three patients (age 35-49) with advanced, refractory (n=2) or transformed (n=1) CTCL who underwent reduced-intensity allo-SCT in the context of active disease. All three survived the peri-transplant period and, despite later having disease relapse, all exhibited evidence of a GVL effect. Relapses of the disease were in the context of immune suppression for graft-versus-host disease (GVHD), and when immune suppression was reduced, responses were regained. A comparison is made of these results to those in a review of the published literature to date. We conclude that while a GVL can be achieved for CTCL with reduced-intensity allogeneic transplantation, the clinical benefits are short lived and novel approaches are required to obtain sustained remissions.

  15. Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients.

    PubMed

    Chen, Xiaohua; Barfield, Raymond; Benaim, Ely; Leung, Wing; Knowles, James; Lawrence, Dawn; Otto, Mario; Shurtleff, Sheila A; Neale, Geoffrey A M; Behm, Frederick G; Turner, Victoria; Handgretinger, Rupert

    2005-01-15

    The extent and rapidity with which T cells are regenerated from graft-derived precursor cells directly influences the incidence of infection and the T-cell-based graft-versus-tumor effect. Measurement of T-cell receptor excision circles (TRECs) in peripheral blood is a means of quantifying recent thymic T-cell production and has been used after transplantation in many studies to estimate thymus-dependent T-cell reconstitution. We hypothesized that the quality of thymic function before transplantation affects thymus-dependent T-cell reconstitution after transplantation. We used real-time polymerase chain reaction (PCR) to quantify signal-joint TRECs (sjTRECs) before and after transplantation. T-cell reconstitution was evaluated by T-cell receptor beta (TCRbeta) CDR3 size spectratyping. We tested 77 healthy sibling donors and 244 samples from 26 pediatric recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Blood from the healthy donors contained 1200 to 155,000 sjTREC copies/mL blood. Patients who had greater than 1200 copies/mL blood before transplantation showed early recovery of sjTREC numbers and TCRbeta repertoire diversity. In contrast, patients who had fewer than 1200 copies/mL blood before transplantation demonstrated significantly slower restoration of thymus-dependent T cells. We conclude that the rate of reconstitution of thymus-dependent T cells is dependent on the competence of thymic function in the recipients before transplantation. Therefore, pretransplantation measurement of sjTREC may provide an important tool for predicting thymus-dependent T-cell reconstitution after transplantation.

  16. Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    ClinicalTrials.gov

    2005-06-23

    I Cell Disease; Fucosidosis; Globoid Cell Leukodystrophy; Adrenoleukodystrophy; Mannosidosis; Niemann-Pick Disease; Pulmonary Complications; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Metachromatic Leukodystrophy; Gaucher's Disease; Wolman Disease

  17. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

    PubMed

    Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

    2015-07-31

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.

  18. Ravuconazole in Preventing Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation

    ClinicalTrials.gov

    2012-03-07

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  19. Functionally Active HIV-Specific T Cells that Target Gag and Nef Can Be Expanded from Virus-Naïve Donors and Target a Range of Viral Epitopes: Implications for a Cure Strategy after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Patel, Shabnum; Lam, Sharon; Cruz, Conrad Russell; Wright, Kaylor; Cochran, Christina; Ambinder, Richard F; Bollard, Catherine M

    2016-03-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) can potentially cure human immunodeficiency virus (HIV) by eliminating infected recipient cells, particularly in the context of technologies that may confer HIV resistance to these stem cells. But, to date, the Berlin patient remains the only case of HIV cure despite multiple attempts to eradicate infection with HSCT. One approach to improve this is to administer virus-specific T cells, a strategy that has proven success in preventing other infections after transplantation. Although we have reported that broadly HIV-specific T cells can be expanded from HIV+ patients, allogeneic transplantations only contain virus-naïve T cells. Modifying this approach for the allogeneic setting requires a robust, reproducible platform that can expand HIV-specific cells from the naïve pool. Hence, we hypothesized that HIV-specific T cells could be primed ex vivo from seronegative individuals to effectively target HIV. Here, we show that ex vivo-primed and expanded HIV-specific T cells released IFNγ in response to HIV antigens and that these cells have enhanced ability to suppress replication in vitro. This is the first demonstration of ex vivo priming and expansion of functional, multi-HIV antigen-specific T cells from HIV-negative donors, which has implications for use of allogeneic HSCT as a functional HIV cure. PMID:26721209

  20. Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload

    ClinicalTrials.gov

    2012-07-16

    Iron Overload; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult

  1. Safety and Efficacy of Pentostatin and Low Dose TBI With Allogenic Peripheral Blood Stem Cell Transplant

    ClinicalTrials.gov

    2010-12-02

    Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndromes; Multiple Myeloma; Non-Hodgkins Lymphoma; Hodgkins Disease; Peripheral T-Cell Lymphoma

  2. Enumeration of NKG2C+ natural killer cells early following allogeneic stem cell transplant recipients does not allow prediction of the occurrence of cytomegalovirus DNAemia.

    PubMed

    Giménez, Estela; Solano, Carlos; Amat, Paula; de la Cámara, Rafael; Nieto, José; López, Javier; Garcia-Noblejas, Ana; Navarro, David

    2015-09-01

    The role of Natural killer (NK) cells in the control of cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients has not been precisely characterized. The current study is aimed at investigating the potential role of NK cells expressing the activating receptor NKG2C in affording protection against the development of CMV DNAemia in patients exhibiting detectable CMV-specific CD8(+) T-cell responses early following transplantation. A total of 61 nonconsecutive patients were included in the study. Peripheral levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells and CMV pp65/IE-1-specific IFN-γ-producing CD8(+) T-cells were enumerated by flow cytometry at days +30 and +60 after transplant. Neither the absolute number of NKG2C(+) NK cells, nor that of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK-cell subsets at day 30 differed significantly between patients with or without subsequent CMV DNAemia. No significant correlation was found between levels of both NKG2C(+) NK-cell populations and the peak CMV DNA load within subsequent episodes of CMV DNAemia. The data indicate that enumeration of NKG2C(+) NK cells early after transplant is unlikely to be helpful in identifying those patients at highest risk of developing CMV DNAemia. Moreover, the data do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia.

  3. Slowly Delivered Icariin/Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells to Promote the Healing of Calvarial Critical-Size Bone Defects

    PubMed Central

    Liu, Tianlin; Luo, Yuan

    2016-01-01

    Bone tissue engineering technique is a promising strategy to repair large-volume bone defects. In this study, we developed a 3-dimensional construct by combining icariin (a small-molecule Chinese medicine), allogeneic bone marrow-derived mesenchymal stem cells (BMSCs), and a siliceous mesostructured cellular foams-poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (SMC-PHBHHx) composite scaffold. We hypothesized that the slowly released icariin could significantly promote the efficacy of SMC-PHBHHx/allogeneic BMSCs for repairing critical-size bone defects in rats. In in vitro cellular experiments, icariin at optimal concentration (10−6 mol/L) could significantly upregulate the osteogenesis- and angiogenesis-related genes and proteins, such as Runx2, ALP, osteocalcin, vascular endothelial growth factors, and fibroblast growth factors, as well as the mineralization of BMSCs. Icariin that was adsorbed onto the SMC-PHBHHx scaffold showed a slow release profile within a 2-week monitoring span. Eight weeks after implantation in calvarial critical-size bone defects, the constructs with icariin were associated with significantly higher bone volume density, trabecular thickness, trabecular number, and significantly lower trabecular separation than the constructs without icariin. Histomorphometric analysis showed that icariin was also associated with a significantly higher density of newly formed blood vessels. These data suggested a promising application potential of the icariin/SMC-PHBHHx/allogeneic BMSCs constructs for repairing large-volume bone defects in clinic. PMID:27721833

  4. Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer

    ClinicalTrials.gov

    2013-03-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Myelodysplastic Syndromes; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Disseminated Neuroblastoma; Malignant Neoplasm; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Immature Teratoma; Ovarian Mature Teratoma; Ovarian Mixed Germ Cell Tumor; Ovarian Monodermal and Highly Specialized Teratoma; Ovarian Polyembryoma; Ovarian Yolk Sac Tumor; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Malignant Testicular Germ Cell Tumor; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Testicular Choriocarcinoma; Testicular Choriocarcinoma and Embryonal Carcinoma; Testicular Choriocarcinoma and Seminoma; Testicular Choriocarcinoma and Teratoma; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma; Testicular

  5. Toxoplasmosis, a severe complication in allogeneic hematopoietic stem cell transplantation: successful treatment strategies during a 5-year single-center experience.

    PubMed

    Roemer, E; Blau, I W; Basara, N; Kiehl, M G; Bischoff, M; Günzelmann, S; Kirsten, D; Sanchez, H; Wocker, E L; Fauser, A A

    2001-01-01

    Toxoplasmosis is a rare but often fatal complication that occurs after patients undergo allogeneic hematopoietic stem cell transplant. At our institution, toxoplasmosis was diagnosed in 8 of 301 patients who received stem cell transplants. Disseminated toxoplasmosis with a rapid fatal course was observed in 2 patients. Six patients had cerebral toxoplasmosis diagnosed on the basis of neurological signs and observation of the patients' mental confusion, seizures, and typical lesions (which were assessed by computed tomography, magnetic resonance imaging, or both). Seroconversion of antitoxoplasma immunoglobulin and a discovery of toxoplasma deoxyribonucleic acid in the cerebrospinal fluid (confirmed by use of polymerase chain reaction) were documented in all patients. Treatment consisted of clindamycin therapy (for 2 patients) and of pyrimethamine-clindamycin therapy, sulfadiazine therapy, or both (for 5 patients). Patients showed improvement after therapy, as assessed by clinical and radiological means. Three of 8 patients survive-1 without any residual neurological symptoms and 2 with minimal neurological symptoms. PMID:11118397

  6. Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies

    ClinicalTrials.gov

    2016-08-15

    SCID; Omenn's Syndrome; Reticular Dysgenesis; Wiskott-Aldrich Syndrome; Bare Lymphocyte Syndrome; Common Variable Immunodeficiency; Chronic Granulomatous Disease; CD40 Ligand Deficiency; Hyper IgM Syndrome; X-linked Lymphoproliferative Disease; Hemophagocytic Lymphohistiocytosis; Griscelli Syndrome; Chediak-Higashi Syndrome; Langerhan's Cell Histiocytosis

  7. The Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Methotrexate Prophylaxis

    PubMed Central

    Shin, Dong-Yeop; Koh, Youngil; Yoon, Sung-Soo; Seong, Moon-Woo; Park, Sung Sup; Kim, Jin Hee; Lee, Yun-Gyoo; Kim, Inho

    2016-01-01

    Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122–2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627–4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as

  8. Ocular graft versus host disease in allogenic haematopoetic stem cell transplantation in a tertiary care centre in India

    PubMed Central

    Khan, Rehan; Nair, Sridevi; Seth, Tullika; Mishra, Pravas; Mahapatra, Manoranjan; Agarwal, Tushar; Tandon, Radhika; Vanathi, Murugesan

    2015-01-01

    Background & objectives: This study was aimed to report the occurrence of ocular graft versus host disease (oGVHD) in allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients in a tertiary care hospital setting. Methods: A cross-sectional study of ocular surface of allo-HSCT patients was done. Slit lamp biomicroscopy, symptom score, tear meniscus height, fluorescein tear break-up time, Schirmer's test I, ocular surface staining, dry eye severity, ocular surface disease index score were done. Indications for allo-HSCT, human leukocyte antigen (HLA) matching, GVHD risk factor, systemic manifestation and treatment were also noted. Results: GVHD occurred in 44.4 per cent of 54 allo-HSCT patients (mean age 26.7 ± 12 yr) included in the study. GVHD risk factors identified included female gender, relapse, older age of donor, cytomagelo virus (CMV) reactivation, and multiparous female donors. oGVHD was noted in 31.5 per cent with mean time to occurrence being 17.8 ± 21.9 months after the allo-HSCT and was observed in 89.5 per cent of chronic GVHD cases. Acute GVHD (oral and dermatological) involvement showed a significant association with GVHD in our patients (P< 0.001, 0R 23.0, CI 6.4-82.1). Chronic GVHD was observed to be associated with the occurrence of oGVHD (dry eye) (P<0.001, OR = 24.0, CI 0.02 - 0.29). Of the 34 eyes with oGHVD, dry eye of level 3 severity was seen in 16, level 2 in six, level 1 in 12 eyes. Interpretation & conclusions: GVHD occurred in 44.4 per cent of the patients studied in the present study. Acute and chronic GVHD showed a strong association with oGVHD. Dry eye disease due to chronic oGVHD was observed in 17 (31.5%) of 54 allo-HSCT patient with chronic oGVHD occurring in 17 (89.4%) of chronic GVHD cases in allo-HSCT patients. Our study on oGVHD in post allo-HSCT patients in tertiary care centre points towards the fact that ocular morbidity due to dry eye disease as a result of oGVHD is a cause for concern in these patients

  9. A matched case-control study of toxoplasmosis after allogeneic haematopoietic stem cell transplantation: still a devastating complication.

    PubMed

    Conrad, A; Le Maréchal, M; Dupont, D; Ducastelle-Leprêtre, S; Balsat, M; Labussière-Wallet, H; Barraco, F; Nicolini, F-E; Thomas, X; Gilis, L; Chidiac, C; Ferry, T; Wallet, F; Rabodonirina, M; Salles, G; Michallet, M; Ader, F

    2016-07-01

    Toxoplasmosis (TXP) is a life-threatening complication of allogeneic haematopoietic stem cell transplantation (AHSCT). Little is known about the risk factors and there is no consensus on prophylactic measures. To investigate the risk factors, we conducted a single-centre, retrospective matched case-control study among adults who underwent AHSCT from January 2006 to March 2015 in our hospital. TXP cases were identified from the prospectively maintained hospital's database. The 1:2 control population consisted of the two patients who received an AHSCT immediately before and after each case with similar donor relationship (related, unrelated) but who did not develop TXP. Risk factors were identified by conditional logistic regression. Clinical features and outcome of TXP were examined. Twenty-three (3.9%) cases of TXP (20 diseases, three infections) were identified among 588 AHSCT recipients. Twenty (87%) cases had a positive pre-transplant Toxoplasma gondii serology. In comparison with 46 matched control patients, risk factors were the absence of effective anti-Toxoplasma prophylaxis (odds ratio (OR) 11.95; 95% CI 3.04-46.88; p <0.001), high-grade (III-IV) acute graft-versus-host-disease (OR 3.1; 95% CI 1.04-9.23; p 0.042) and receipt of the tumour necrosis factor-α blocker etanercept (OR 12.02; 95% CI 1.33-108.6; p 0.027). Mortality attributable to TXP was 43.5% (n = 10). Non-relapse mortality rates during the study period of cases and controls were 69.6% (n = 16) and 17.4% (n = 8), respectively. Lung involvement was the dominant clinical feature (n = 14). Two cases were associated with graft failure, one preceded by haemophagocytic syndrome. Given TXP-related morbidity and attributable mortality, anti-Toxoplasma prophylaxis is essential for optimized management of seropositive AHSCT recipients. PMID:27172809

  10. Long-term outcome after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with multiple myeloma.

    PubMed

    El-Cheikh, Jean; Crocchiolo, Roberto; Furst, Sabine; Stoppa, Anne-Marie; Ladaique, Patrick; Faucher, Catherine; Calmels, Boris; Lemarie, Claude; De Colella, Jean-Marc Schiano; Granata, Angela; Coso, Diane; Bouabdallah, Reda; Chabannon, Christian; Blaise, Didier

    2013-05-01

    This study examines the long-term outcomes of a cohort of patients with myeloma who were treated with reduced-intensity conditioning (RIC) regimens after a minimum follow-up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem-cell transplantation (Allo-SCT) between January 2000 and January 2007 were identified. The median follow-up of living patients was 84 months (51-141). The median age of the MM patients was 50 (28-70) years. Fifty-one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo-SCT was 34 months (6-161), and the median time between auto-SCT and Allo-SCT was 10 months (1-89). Fifty-one patients (96%) received at least one auto-SCT; 24 patients (45%) received a tandem auto-Allo-SCT. At last follow-up, 21 patients (40%) are alive > 5 years post RIC Allo-SCT. At last follow-up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re-induction with one of the new anti-myeloma drugs (bortezomib or lenalidomide) after Allo-SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo-SCT. Disease status and occurrence of cGvHD were significantly associated with progression-free survival (PFS); hazard ratio (HR) = 0.62 (0.30-1.29, P = 0.20). Acute GvHD was correlated with higher transplant-related mortality; HR = 4.19 (1.05-16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long-term disease control can be expected in a subset of MM patients undergoing RIC Allo-SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo-SCT stabilizes in time with a plateau after 6 years post Allo-SCT.

  11. Immunosuppressive Total Lymphoid Irradiation-Based Reconditioning Regimens Enable Engraftment After Graft Rejection or Graft Failure in Patients Treated With Allogeneic Hematopoietic Stem Cell Transplantation

    SciTech Connect

    Heinzelmann, Frank; Lang, Peter J.; Ottinger, Hellmut; Faul, Christoph; Bethge, Wolfgang; Handgretinger, Rupert; Bamberg, Michael; Belka, Claus

    2008-02-01

    Purpose: To retrospectively evaluate the efficacy of total lymphoid irradiation (TLI)-based reconditioning regimens in patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation. Methods and Materials: The results of 14 patients (7 adults and 7 children) with a variety of hematologic malignant diseases treated with a TLI-based reconditioning regimen with 7-Gy single-dose application plus anti-T-lymphocyte antibody OKT3 (n = 11) and/or antithymocyte globulin (n = 7)/fludarabine (n = 9), followed by an infusion of peripheral blood stem cells (n = 13) or bone marrow stem cells (n = 1) from related or unrelated donors, were retrospectively analyzed. Results: Of the 14 recipients, the data from 11 were evaluable for engraftment after TLI-based reconditioning because 3 adults died early (at Day 2, 5, and 15) after the second transplantation of infectious complications. Engraftment in 4 adults was seen after a median of 12 days (range, 10-18) and occurred after a median of 10 days (range, 9-32) in the 7 children. TLI-based reconditioning was well-tolerated with no severe toxicity. The median overall survival and disease-free survival for the whole cohort was 140 days (range, 5-1,268). After a median follow-up of 681 days, the disease-free survival and overall survival rate was 85.7% and 85.7%, respectively, in the children. Despite engraftment in the 4 remaining adults, 1 died of fatal graft-vs.-host disease, 1 of infectious complications, 1 of disease relapse, and 1 of acute respiratory distress syndrome. Conclusions: In patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation, TLI-based reconditioning regimens allow sustained engraftment, paralleled by a favorable toxicity profile, potentially leading to long-term survival.

  12. Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies.

    PubMed

    Abbasalizadeh, Saeed; Baharvand, Hossein

    2013-12-01

    Recent technological advances in the generation, characterization, and bioprocessing of human pluripotent stem cells (hPSCs) have created new hope for their use as a source for production of cell-based therapeutic products. To date, a few clinical trials that have used therapeutic cells derived from hESCs have been approved by the Food and Drug Administration (FDA), but numerous new hPSC-based cell therapy products are under various stages of development in cell therapy-specialized companies and their future market is estimated to be very promising. However, the multitude of critical challenges regarding different aspects of hPSC-based therapeutic product manufacturing and their therapies have made progress for the introduction of new products and clinical applications very slow. These challenges include scientific, technological, clinical, policy, and financial aspects. The technological aspects of manufacturing hPSC-based therapeutic products for allogeneic and autologous cell therapies according to good manufacturing practice (cGMP) quality requirements is one of the most important challenging and emerging topics in the development of new hPSCs for clinical use. In this review, we describe main critical challenges and highlight a series of technological advances in all aspects of hPSC-based therapeutic product manufacturing including clinical grade cell line development, large-scale banking, upstream processing, downstream processing, and quality assessment of final cell therapeutic products that have brought hPSCs closer to clinical application and commercial cGMP manufacturing.

  13. Early recipient chimerism testing in the T- and NK-cell lineages for risk assessment of graft rejection in pediatric patients undergoing allogeneic stem cell transplantation.

    PubMed

    Breuer, S; Preuner, S; Fritsch, G; Daxberger, H; Koenig, M; Poetschger, U; Lawitschka, A; Peters, C; Mann, G; Lion, T; Matthes-Martin, S

    2012-03-01

    Timely diagnosis of impending graft rejection is crucial for effective therapeutic intervention after allogeneic hematopoietic stem cell transplantation (SCT). We have investigated the predictive potential of early leukocyte subset-specific chimerism for graft loss in children undergoing SCT. In total, 192 pediatric patients transplanted for the treatment of malignant and non-malignant diseases after reduced-intensity or myeloablative conditioning were investigated. Surveillance of lineage-specific chimerism was initiated upon first appearance of leukocyte counts amenable to cell sorting. Graft rejection occurred in 23 patients between 24 and 492 days post-transplant (median 63 days). The first chimerism analysis of T and NK cells performed at a median of 20 days after SCT identified three different risk groups that were independent from the conditioning regimen: recipient chimerism (RC) levels in T cells below 50% indicated a very low risk of rejection (1.4%), whereas high levels of RC (>90%) both in T and NK cells heralded graft loss in the majority of patients (90%) despite therapeutic interventions. RC >50% in T cells and ≤90% in NK cells defined an intermediate-risk group in which timely immunotherapy frequently prevented rejection. Early assessment of T- and NK-cell chimerism can therefore be instrumental in the risk assessment and therapeutic management of imminent graft rejection.

  14. Pretransplantation fluorine-18-deoxyglucose--positron emission tomography scan lacks prognostic value in chemosensitive B cell non-hodgkin lymphoma patients undergoing nonmyeloablative allogeneic stem cell transplantation.

    PubMed

    Sauter, Craig S; Lechner, Lauren; Scordo, Michael; Zheng, Junting; Devlin, Sean M; Fleming, Stephen E; Castro-Malaspina, Hugo; Moskowitz, Craig H

    2014-06-01

    Whether chemosensitivity, as determined by positron emission tomography using fluorine-18-deoxyglucose (FDG-PET), is a requirement for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) has yet to be established. We analyzed 88 patients with B cell non-Hodgkin lymphoma (B-NHL) for event-free (EFS) and overall survival (OS) according to computed tomography (CT) and FDG-PET criteria before uniform nonmyeloablative (NMA) allo-SCT. Patients who were chemosensitive, according to CT criteria, experienced significantly greater EFS (P < .001) and OS (P < .03) compared with those who were chemorefractory at the time of allo-SCT. Of 58 patients within this cohort who were chemosensitive by CT criteria, there was no difference in EFS (P = .85) or OS (P = .96) between FDG-PET-positive (Deauville 4 to 5, n = 24) and FDG-PET-negative (Deauville 1 to 3, n = 34) patients. There was no difference in survival according to age < or ≥ 60 years, prior autologous-stem cell transplantation, allograft characteristics, or histology. FDG-PET adds no prognostic value in chemosensitive B-NHL before NMA-allo-SCT.

  15. NCI 1st International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Summary and Recommendations from the Organizing Committee

    PubMed Central

    Bishop, Michael R.; Alyea, Edwin P.; Cairo, Mitchell S.; Falkenburg, J.H. Frederik; June, Carl H.; Kröger, Nicolaus; Little, Richard F.; Miller, Jeffrey S.; Pavletic, Steven Z.; Porter, David L.; Riddell, Stanley R.; van Besien, Koen; Wayne, Alan S.; Weisdorf, Daniel J.; Wu, Roy S.; Giralt, Sergio

    2011-01-01

    The First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT). Each of the Workshop’s six working committees have published individual reports of ongoing basic, translational and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention and treatment. This document summarizes each of the committees’ recommendations and suggests three major initiatives for a coordinated research effort to address the problem of relapse after alloHSCT. The first is the need to establish multi-center correlative and clinical trials networks for basic/translational, epidemiological, and clinical research. Second, there is a need for a network of biorepositories for the collection of samples pre- and post-alloHSCT to aid in laboratory and clinical studies. Third, there should be further refinement, implementation, and study of the proposed Workshop disease-specific response and relapse definitions and the recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplant organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse following alloHSCT. PMID:21224011

  16. Transmission of an expanding donor-derived del(20q) clone through allogeneic hematopoietic stem cell transplantation without the development of a hematologic neoplasm.

    PubMed

    Aikawa, Vania; Porter, David; Luskin, Marlise R; Bagg, Adam; Morrissette, Jennifer J D

    2015-12-01

    Donor cell leukemia is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT), which may result from the development of a new malignancy in previously healthy donor cells after transplant into the recipient, or it may derive from the transmission of an occult leukemia from donor to recipient. We report a case of donor derived 20q11.2 deletion in a male patient who received an allogeneic HSCT from his HLA-identical sister for the treatment of his chronic lymphocytic leukemia. Bone marrow cells from the donor were found to contain the 20q deletion that expanded over time, but which was absent in her peripheral blood cells. Although cases of donor cell leukemia after HSCT have been reported, in this case there has been no evidence of an associated hematologic neoplasm in either the donor or recipient. Pre-transplant donor bone marrow evaluations are not practical or warranted, however the finding of new cytogenetic abnormalities after transplant mandates a thorough evaluation of the donor.

  17. Clinical Outcomes Associated With Respiratory Virus Detection Before Allogeneic Hematopoietic Stem Cell Transplant

    PubMed Central

    Campbell, Angela P.; Guthrie, Katherine A.; Englund, Janet A.; Farney, Robert M.; Minerich, Elisa L.; Kuypers, Jane; Corey, Lawrence; Boeckh, Michael

    2015-01-01

    Background. The management of respiratory virus infections prior to hematopoietic cell transplant (HCT) is difficult. We examined whether respiratory virus detection before HCT influenced the requirement for bronchoscopy, hospitalization, and overall survival following HCT. Methods. Pre-HCT and weekly post-HCT nasal washes were collected through day 100 from patients with and without symptoms. Samples were tested by multiplex polymerase chain reaction for respiratory syncytial virus, parainfluenza viruses 1–4, influenza A and B, human metapneumovirus, adenovirus, and human rhinoviruses, coronaviruses, and bocavirus. Results. Of 458 patients, 116 (25%) had respiratory viruses detected pre-HCT. Overall, patients with viruses detected pre-HCT had fewer days alive and out of the hospital and lower survival at day 100 (adjusted hazard ratio [aHR], 2.4; 95% confidence interval [CI], 1.3–4.5; P = .007) than patients with negative samples; this risk was also present with rhinovirus alone (aHR for mortality, 2.6; 95% CI, 1.2–5.5; P = .01). No difference in bronchoscopy incidence was seen in patients with and without respiratory viruses (aHR, 1.3; 95% CI, .8–2.0; P = .32). In symptomatic patients, those with respiratory viruses detected had increased overall mortality compared with patients without viruses detected (unadjusted HR, 3.5; 95% CI, 1.0–12.1; P = .05); among asymptomatic patients, detection of respiratory viruses was not associated with increased mortality. Conclusions. These data support routine testing for respiratory viruses among symptomatic patients before HCT, and delay of transplant with virus detection when feasible, even for detection of rhinovirus alone. Further study is needed to address whether asymptomatic patients should undergo screening for respiratory virus detection before HCT. PMID:25847977

  18. Present and Future of Allogeneic Natural Killer Cell Therapy

    PubMed Central

    Lim, Okjae; Jung, Mi Young; Hwang, Yu Kyeong; Shin, Eui-Cheol

    2015-01-01

    Natural killer (NK) cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation revealed the antitumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions. PMID:26089823

  19. Combined CD4+ Donor Lymphocyte Infusion and Low-Dose Recombinant IL-2 Expand FOXP3+ Regulatory T Cells following Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Zorn, Emmanuel; Mohseni, Mehrdad; Kim, Haesook; Porcheray, Fabrice; Lynch, Allison; Bellucci, Roberto; Canning, Christine; Alyea, Edwin P.; Soiffer, Robert J.; Ritz, Jerome

    2009-01-01

    CD4+CD25+FOXP3+ regulatory T cells (Treg) successfully control graft-versus-host-disease (GVHD) in animal models. In humans, incomplete reconstitution of Treg after allogeneic hematopoietic stem cell transplantation (HSCT) has been associated with chronic GVHD. Recent studies have demonstrated that IL-2 infusions expand Treg in vivo. However, the effectiveness of this therapy depends on the number of cells capable of responding to IL-2. We examined the effect of low-dose IL-2 infusions on Treg populations after HSCT in patients who also received infusions of donor CD4+ lymphocytes. Utilizing FOXP3 as a Treg marker, we found that patients who received CD4+DLI concomitantly with IL-2 had greater expansion of Treg compared to patients who received IL-2 (p=0.03) or CD4+DLI alone (p=0.001). FOXP3 expression correlated with absolute CD4+CD25+ cell counts. Moreover, expanded CD4+CD25+ T cells displayed normal suppressive function and treatment with CD4+DLI and IL-2 was not associated with GVHD. This study suggests that administration of low-dose IL-2 combined with adoptive CD4+ cellular therapy may provide a mechanism to expand Treg in vivo. PMID:19203731

  20. Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation

    PubMed Central

    Fellowes, Vicki; Rose, Jeremy J.; Odom, Jeanne; Pittaluga, Stefania; Steinberg, Seth M.; Blacklock-Schuver, Bazetta; Avila, Daniele N.; Memon, Sarfraz; Kurlander, Roger J.; Khuu, Hahn M.; Stetler-Stevenson, Maryalice; Mena, Esther; Dwyer, Andrew J.; Levine, Bruce L.; June, Carl H.; Reshef, Ran; Vonderheide, Robert H.; Gress, Ronald E.; Fowler, Daniel H.; Hakim, Frances T.; Bishop, Michael R.

    2012-01-01

    Donor lymphocyte infusion (DLI), a standard relapse treatment after allogeneic stem cell transplantation (AlloSCT), has limited efficacy and often triggers GVHD. We hypothesized that after AlloSCT tumor-infiltrating donor lymphocytes could be costimulated ex vivo to preferentially activate/expand antitumor effectors. We tested the feasibility and safety of costimulated, tumor-derived donor lymphocyte (TDL) infusion in a phase 1 trial. Tumor was resected from 8 patients with B-cell malignancy progression post-AlloSCT; tumor cell suspensions were costimulated with anti-CD3/anti-CD28 Ab-coated magnetic beads and cultured to generate TDL products for each patient. Costimulation yielded increased proportions of T-bet+FoxP3− type 1 effector donor T cells. A median of 2.04 × 107 TDL/kg was infused; TDLs were well tolerated, notably without GVHD. Two transient positron emission tomography (PET) responses and 2 mixed responses were observed in these refractory tumors. TDL are a feasible, tolerable, and novel donor cell therapy alternative for relapse after AlloSCT. This trial is registered at clinicaltrials.gov as no. NCT00445666. PMID:22289893

  1. Donor Chimerism of B Cells and Nature Killer Cells Provides Useful Information to Predict Hematologic Relapse following Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Jiang, Ying; Wan, Liping; Qin, Youwen; Wang, Xiaorui; Yan, Shike; Xie, Kuangcheng; Wang, Chun

    2015-01-01

    In this study we investigated the correlation between donor chimerism status and disease relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The chimerism of Fluorescence-activated cell sorter (FACS) sorted CD3+T lymphocytes of 153 cases, CD56+CD16+NK lymphocytes of 153 cases and CD19+B lymphocytes of 31 cases with acute B lymphoblastic leukemia (B-ALL) was analyzed post-transplant utilizing polymerase chain reaction amplification of short tandem repeats (PCR-STR). A total of 33 patients (33/153, 21.6%) had recurrent disease. The positive predictive values of declining donor chimerism for hematologic and isolated extramedullary relapse were 58.8% and 10% (P=0.018, Chi-Square). The positive predictive values of declining donor chimerism in BMB, BMT, BMNK and PBB for hematologic relapse were 11.6%, 0%, 0% and 0% under close monitoring in patients with B-ALL. Only the donor chimerism in BMB significantly decreased in the group with hematologic relapse as compared with the group without hematologic relapse (P=0.00, Independent-samples T test) in patients with B-ALL. The median drop of donor chimerism in PBT, BMT, PBNK and BMNK were 0%, 0%, 5.9% and 2.8% one or two weeks prior to hematologic relapse in patients with non-B-ALL. The donor chimerism in PBNK significantly decreased prior to hematologic relapse in the group with hematologic relapse as compared with the group without hematologic relapse (P=0.022, Independent-samples T test).These data suggest donor chimerism of BMB can be used to predict the occurrence of hematologic relapse in patients with B-ALL. Donor chimerism decrease in PBNK was associated with a somewhat increased risk of hematologic relapse in patients with non-B-ALL. Therefore, our results reveal a more effective path to individually predict for hematologic relapse by dynamic monitoring different cell lineages in different disease.

  2. Real-time qPCR for chimerism assessment in allogeneic hematopoietic stem cell transplants from unrelated adult and double umbilical cord blood.

    PubMed

    Frankfurt, Olga; Zitzner, Jennifer R; Tambur, Anat R

    2015-03-01

    Allogeneic hematopoietic stem cell transplantation is the standard therapy for patients with various malignant hematologic disorders. A successful treatment results in complete engraftment of donor cells in the absence of the patient's own hematopoietic system. Chimerism analysis, aimed at determining the coexistence of genetically different cell populations, is considered a useful method to measure treatment success. A new, qPCR based, commercially available chimerism assay was recently introduced. Here we report our results of comparing STR with qPCR-based chimerism analysis, and assessment of sensitivity and reproducibility of the qPCR chimerism assay. A specific emphasis is put on analyzing chimerism in recipients of double cord blood transplantation. We conclude that the qPCR chimerism assay for engraftment monitoring is a reliable and sensitive assay. Advantages and limitations of the assay in its current format are summarized.

  3. Allogeneic Murine Mesenchymal Stem Cells: Migration to Inflamed Joints In Vivo and Amelioration of Collagen Induced Arthritis When Transduced to Express CTLA4Ig

    PubMed Central

    Barry, Frank; Ritter, Thomas; O'Flatharta, Cathal; Howard, Linda; Shaw, Georgina; Anegon, Ignacio; Murphy, Mary

    2013-01-01

    Despite the immunosuppressive, homing, and regenerative capabilities of mesenchymal stem cells (MSCs), their ability to migrate to arthritic joints and influence the course of arthritis in vivo remains poorly understood. The objective of this study was to determine if allogeneic MSCs migrate to inflamed joints in vivo and to determine if MSCs expressing the costimulation blocker cytotoxic T lymphocyte associated antigen-4 coupled to immunoglobulin-G (CTLA4Ig) could be used to ameliorate collagen induced arthritis (CIA). The migration of systemically delivered inbred mouse strain (FVB) MSCs to migrate to inflamed joints in CIA was studied using real-time quantitative polymerase chain reaction. Furthermore, the effect of BALB/c MSCs modified with an adenoviral vector to express CTLA4Ig, on T cell function in vitro and on CIA in vivo was assessed. After systemic delivery of FVB MSCs, eGFP DNA was detectable in the joints of mice with CIA confirming that some MSCs had reached to inflamed joints. BALB/c MSCs suppressed the secretion of both TNFα and IFNγ, and reduced the ratio of Th1:Th2 cytokine expression, by DBA/1 T cells in vitro irrespective of viral modification. The expression of CTLA4Ig did not augment this effect. Despite a worsening of disease scores after infusion of BALB/c MSCs in vivo, BALB/c MSCs expressing CTLA4Ig significantly delayed the onset of inflammatory arthritis in CIA. These data demonstrate that allogeneic MSCs can migrate to the inflamed joints of CIA in vivo and that genetically modified allogeneic MSCs may be considered for development of gene therapy strategies for inflammatory arthritis PMID:23895495

  4. Allogeneic Transplantation of an Adipose-Derived Stem Cell Sheet Combined With Artificial Skin Accelerates Wound Healing in a Rat Wound Model of Type 2 Diabetes and Obesity.

    PubMed

    Kato, Yuka; Iwata, Takanori; Morikawa, Shunichi; Yamato, Masayuki; Okano, Teruo; Uchigata, Yasuko

    2015-08-01

    One of the most common complications of diabetes is diabetic foot ulcer. Diabetic ulcers do not heal easily due to diabetic neuropathy and reduced blood flow, and nonhealing ulcers may progress to gangrene, which necessitates amputation of the patient's foot. This study attempted to develop a new cell-based therapy for nonhealing diabetic ulcers using a full-thickness skin defect in a rat model of type 2 diabetes and obesity. Allogeneic adipose-derived stem cells (ASCs) were harvested from the inguinal fat of normal rats, and ASC sheets were created using cell sheet technology and transplanted into full-thickness skin defects in Zucker diabetic fatty rats. The results indicate that the transplantation of ASC sheets combined with artificial skin accelerated wound healing and vascularization, with significant differences observed 2 weeks after treatment. The ASC sheets secreted large amounts of several angiogenic growth factors in vitro, and transplanted ASCs were observed in perivascular regions and incorporated into the newly constructed vessel structures in vivo. These results suggest that ASC sheets accelerate wound healing both directly and indirectly in this diabetic wound-healing model. In conclusion, allogeneic ASC sheets exhibit potential as a new therapeutic strategy for the treatment of diabetic ulcers.

  5. Chimerism in DNA of buccal swabs from recipients after allogeneic hematopoietic stem cell transplantations: implications for forensic DNA testing.

    PubMed

    Berger, Burkhard; Parson, Roswitha; Clausen, Johannes; Berger, Cordula; Nachbaur, David; Parson, Walther

    2013-01-01

    We attempted to quantitatively determine the chimeric state in a total of 162 buccal swabs from 77 adult recipients aged 19-74 (median 50 years) after allogeneic hematopoietic cell transplantation by estimating the chimeric recipient/donor DNA ratios through analysis of 15 autosomal short tandem repeat markers. From each individual between one and nine, buccal swabs were taken at known time intervals after transplantation, ranging from 17 to 3,361 days (median 394 days). In buccal cells, the determined recipient/donor DNA ratios turned out to be highly variable between individuals and also within an individual. Relative donor chimerism levels (%Ch) between 0 and 100 % were detected with maximal frequencies between 10 and 30 %. Blood was always found to show the donor's genotype while hair samples in all cases gave the recipient's genotype. We examine chimerism levels with respect to age, gender, and posttransplantation period and discuss the results in the context of forensic identity testing.

  6. Stem Cell Research.

    PubMed

    Trounson, Alan; Kolaja, Kyle; Petersen, Thomas; Weber, Klaus; McVean, Maralee; Funk, Kathleen A

    2015-01-01

    Stem cells have great potential in basic research and are being slowly integrated into toxicological research. This symposium provided an overview of the state of the field, stem cell models, described allogenic stem cell treatments and issues of immunogenicity associated with protein therapeutics, and tehn concentrated on stem cell uses in regenerative medicine focusing on lung and testing strategies on engineered tissues from a pathologist's perspective.

  7. Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia

    PubMed Central

    Preuner, Sandra; Peters, Christina; Pötschger, Ulrike; Daxberger, Helga; Fritsch, Gerhard; Geyeregger, Rene; Schrauder, André; von Stackelberg, Arend; Schrappe, Martin; Bader, Peter; Ebell, Wolfram; Eckert, Cornelia; Lang, Peter; Sykora, Karl-Walter; Schrum, Johanna; Kremens, Bernhard; Ehlert, Karoline; Albert, Michael H.; Meisel, Roland; Lawitschka, Anita; Mann, Georg; Panzer-Grümayer, Renate; Güngör, Tayfun; Holter, Wolfgang; Strahm, Brigitte; Gruhn, Bernd; Schulz, Ansgar; Woessmann, Wilhelm; Lion, Thomas

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13–5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34+ and CD8+ cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34+ and CD8+ leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.trials.gov with the number NC01423747. PMID:26869631

  8. Rapid reconstitution of functionally active 6-sulfoLacNAc+ dendritic cells (slanDCs) of donor origin following allogeneic haematopoietic stem cell transplant

    PubMed Central

    Mimiola, E; Marini, O; Perbellini, O; Micheletti, A; Vermi, W; Lonardi, S; Costantini, C; Meneghelli, E; Andreini, A; Bonetto, C; Vassanelli, A; Cantini, M; Zoratti, E; Massi, D; Zamo', A; Leso, A; Quaresmini, G; Benedetti, F; Pizzolo, G; Cassatella, M A; Tecchio, C

    2014-01-01

    The role of dendritic cells (DCs) and macrophages in allogeneic haematopoietic stem cell transplant (HSCT) is critical in determining the extent of graft-versus-host response. The goal of this study was to analyse slanDCs, a subset of human proinflammatory DCs, in haematopoietic stem cell (HSC) sources, as well as to evaluate their 1-year kinetics of reconstitution, origin and functional capacities in peripheral blood (PB) and bone marrow (BM) of patients who have undergone HSCT, and their presence in graft-versus-host disease (GVHD) tissue specimens. slanDCs were also compared to myeloid (m)DCs, plasmacytoid (p)DCs and monocytes in HSC sources and in patients' PB and BM throughout reconstitution. slanDCs accounted for all HSC sources. In patients' PB and BM, slanDCs were identified from day +21, showing median frequencies comparable to healthy donors, donor origin and kinetics of recovery similar to mDCs, pDCs, and monocytes. Under cyclosporin treatment, slanDCs displayed a normal pattern of maturation, and maintained an efficient chemotactic activity and capacity of releasing tumour necrosis factor (TNF)-α upon lipopolysaccharide (LPS) stimulation. None the less, they were almost undetectable in GVHD tissue specimens, being present only in intestinal acute GVHD samples. slanDCs reconstitute early, being donor-derived and functionally competent. The absence of slanDCs from most of the GVHD-targeted tissue specimens seems to rule out the direct participation of these cells in the majority of the local reactions characterizing GVHD. PMID:24853271

  9. Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia.

    PubMed

    Wang, Q; Qian, S; Li, J; Che, N; Gu, L; Wang, Q; Liu, Y; Mei, H

    2015-10-01

    Autologous hematopoietic stem cell (HSC) and mesenchymal stem cell (MSC) transplantation is currently being evaluated as a novel treatment for autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we report a case of autologous HSC transplantation combined with MSCs in a 25-year-old severe SLE patient with multiple life-threatening complications and refractory to conventional cyclophosphamide (CYC) therapy. After being pretreated with CYC, fludarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient's clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. Moreover, CD4+CD25+FoxP3+Treg cells increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This result suggests that the combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission. Although a longer follow-up is required for assessing the long-term efficacy, our present results suggest that the combined transplantation of HSCs and MSCs may be a novel and effective therapy for refractory SLE.

  10. EBV-negative aggressive B-cell lymphomas of donor origin after allogeneic hematopoietic stem cell transplantation: a report of three cases.

    PubMed

    Federmann, Birgit; Bonzheim, Irina; Schittenhelm, Jens; Quintanilla-Martínez, Leticia; Mankel, Barbara; Vogel, Wichard; Faul, Christoph; Bethge, Wolfgang; Fend, Falko

    2016-11-01

    Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of iatrogenic immunosuppression, and the majority is associated with EBV. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HCT) are rare. Most cases are donor-derived, reflecting immune reconstitution by malignant transformed donor cells, and are EBV-positive. We report three unusual cases of aggressive EBV-negative PTLD of monomorphic type after allo-HCT. All cases were of donor origin and arose with long latency, 4-12 years after HCT. The patients had a history of severe graft-versus-host disease (GVHD) resulting in prolonged immunosuppression before the diagnosis of lymphoma. In one case, the temporal evolution of the malignant clone was analyzed by clone-specific PCR targeting the immunoglobulin heavy chain rearrangement. A tumor-specific product was already detected 3 years before lymphoma development. This indicates that chronic antigenic stimulation and reduced immune surveillance, may promote the outgrowth of premalignant donor-derived clones after acquisition of additional genetic alterations.

  11. Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the Severe Aplastic Anaemia Working Party of the European Society for Blood and Marrow Transplantation.

    PubMed

    Cesaro, Simone; Peffault de Latour, Regis; Tridello, Gloria; Pillon, Marta; Carlson, Kristina; Fagioli, Franca; Jouet, Jean-Pierre; Koh, Mickey B C; Panizzolo, Irene Sara; Kyrcz-Krzemien, Slawomira; Maertens, Johan; Rambaldi, Alessandro; Strahm, Brigitte; Blaise, Didier; Maschan, Alexei; Marsh, Judith; Dufour, Carlo

    2015-11-01

    We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17 days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3·5 years, the 5-year overall survival (OS) was 60·7%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score ≥80 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases.

  12. Influence of genetic polymorphisms of cytokine genes in the outcome of HLA-matched allogeneic stem cell transplantation in a South East Asian population.

    PubMed

    Gan, G G; Leong, Y C; Bee, P C; Chin, E F M; Abdul Halim, H; Nadarajan, V S; Teh, A K H

    2016-02-01

    Non-HLA gene polymorphisms have been shown to be associated with the risk of graft-versus-host disease (GVHD) and outcome of allogeneic haematopoietic stem cell transplantation (AHSCT). This study aims to investigate the role of IL6, TNFα, IL10, IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. A total of 67 patients and 59 donors who underwent HLA-identical matched sibling AHSCT were available for analysis. There was no significant association between the different cytokine genotypes of patients with the incidence and severity of acute GVHD. Patients with IL2 166∗T allele and patients who received donor stem cells who had IL2 166∗G allele appeared to have reduced incidence of cGVHD. Patients who received donor stem cells with IL12 1188∗C allele are found to be associated with better disease free survival. These results suggest a possible role of IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. PMID:26638029

  13. Phase I study of the safety and pharmacokinetics of plerixafor in children undergoing a second allogeneic hematopoietic stem cell transplantation for relapsed or refractory leukemia

    PubMed Central

    Srinivasan, Ashok; Panetta, John C.; Cross, Shane; Pillai, Asha; Triplett, Brandon M.; Shook, Dave R.; Dallas, Mari H.; Hartford, Christine; Sunkara, Anusha; Kang, Guolian; Jacobsen, Jeffrey; Choi, John; Leung, Wing

    2015-01-01

    The safety, pharmacokinetics and biological effect of plerixafor in children as part of a conditioning regimen for chemo-sensitization in allogeneic hematopoietic stem cell transplantation (HSCT) have not been studied. This is a phase I study of plerixafor designed to evaluate its tolerability at dose of 0.24 mg/kg given intravenously on day -4 (level 1), day -4, and day -3 (level 2), or day -4, -3, and day -2 (level 3) in combination with fludarabine, thiotepa, melphalan, and rabbit anti-thymocytic globulin for a second allogeneic HSCT in children with refractory or relapsed leukemia. Immunophenotype analysis was performed on blood and bone marrow prior to and after plerixafor administration. Twelve patients were enrolled. Plerixafor at all 3 levels was well tolerated without dose-limiting toxicity. Transient gastrointestinal side effects of National Cancer Institute grade 1 or 2 in severity were the most common adverse events. The area under the concentration-time curve increased proportionally to the dose level. Plerixafor clearance was higher in males, and increased linearly with body weight, and glomerular filtration rate. The clearance decreased and the elimination half-life increased significantly from dose level 1 to 3 (P < 0.001). Biologically, the proportion of CXCR4-positive blasts and lymphocytes both in the bone marrow and peripheral blood, increased after plerixafor administration. PMID:24769325

  14. Allogeneic stem cell transplantation in a blast-phase chronic myeloid leukemia patient with carbapenem-resistant Klebsiella pneumoniae tricuspid valve endocarditis: A case report

    PubMed Central

    Kantarcioglu, Bulent; Bekoz, Huseyin Saffet; Olgun, Fatih Erkam; Cakal, Beytullah; Arkan, Burak; Turkoglu, Halil; Mert, Ali; Sargin, Deniz

    2016-01-01

    In chronic myeloid leukemia (CML), the occurrence of blastic transformation is rare. Treatment outcome is generally poor. Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment option for advanced-phase CML. Infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates are associated with high morbidity and mortality rates, particularly in patients with haematological malignancies. Infection and colonization by these multiresistant bacteria may represent a challenge in SCT recipients for the management of post-transplantation complications, as well as for the eligibility to receive a transplant in patients who acquire the pathogen prior to the procedure. We herein report the case of a blast-phase CML patient with a highly resistant, CRKP-associated tricuspid valve endocarditis, who was treated with a combination of systemic antimicrobial therapy and surgical valve repair, and subsequently underwent a successful allo-SCT.

  15. Fatal strongyloides hyperinfection complicating a gram-negative sepsis after allogeneic stem cell transplantation: a case report and review of the literature.

    PubMed

    Izquierdo, Isabel; Briones, Javier; Lluch, Rafael; Arqueros, Cristina; Martino, Rodrigo

    2013-01-01

    Strongyloides stercoralis is an intestinal nematode that causes strongyloidiasis, which affects 30 to 100 million people worldwide. Risk factors for hyperinfection and disseminated disease include immunosuppressive drug therapy, human T-lymphotropic virus-1 (HTLV-1) infection, solid organ and bone marrow transplantation, hematologic malignant diseases, hypogammaglobulinemia, and severe malnutrition and associated conditions. The diagnosis can be difficult because a single stool examination fails to detect larvae in up to 70% of the cases, and the symptoms are nonspecific. Although eosinophilia is a common finding in patients with chronic Strongyloides infection, it is an unreliable predictor of hyperinfection. Furthermore, the lack of eosinophilia while receiving immunosuppressive therapy cannot reliably exclude the underlying chronic Strongyloides infection. We report here a fatal Strongyloides hyperinfection in a patient receiving allogeneic stem cell transplantation; risk factors and outcome in this clinical setting are discussed. PMID:23936693

  16. Fatal Strongyloides Hyperinfection Complicating a Gram-Negative Sepsis after Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature

    PubMed Central

    Briones, Javier; Lluch, Rafael; Arqueros, Cristina; Martino, Rodrigo

    2013-01-01

    Strongyloides stercoralis is an intestinal nematode that causes strongyloidiasis, which affects 30 to 100 million people worldwide. Risk factors for hyperinfection and disseminated disease include immunosuppressive drug therapy, human T-lymphotropic virus-1 (HTLV-1) infection, solid organ and bone marrow transplantation, hematologic malignant diseases, hypogammaglobulinemia, and severe malnutrition and associated conditions. The diagnosis can be difficult because a single stool examination fails to detect larvae in up to 70% of the cases, and the symptoms are nonspecific. Although eosinophilia is a common finding in patients with chronic Strongyloides infection, it is an unreliable predictor of hyperinfection. Furthermore, the lack of eosinophilia while receiving immunosuppressive therapy cannot reliably exclude the underlying chronic Strongyloides infection. We report here a fatal Strongyloides hyperinfection in a patient receiving allogeneic stem cell transplantation; risk factors and outcome in this clinical setting are discussed. PMID:23936693

  17. Allogeneic stem cell transplantation in a blast-phase chronic myeloid leukemia patient with carbapenem-resistant Klebsiella pneumoniae tricuspid valve endocarditis: A case report

    PubMed Central

    Kantarcioglu, Bulent; Bekoz, Huseyin Saffet; Olgun, Fatih Erkam; Cakal, Beytullah; Arkan, Burak; Turkoglu, Halil; Mert, Ali; Sargin, Deniz

    2016-01-01

    In chronic myeloid leukemia (CML), the occurrence of blastic transformation is rare. Treatment outcome is generally poor. Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment option for advanced-phase CML. Infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates are associated with high morbidity and mortality rates, particularly in patients with haematological malignancies. Infection and colonization by these multiresistant bacteria may represent a challenge in SCT recipients for the management of post-transplantation complications, as well as for the eligibility to receive a transplant in patients who acquire the pathogen prior to the procedure. We herein report the case of a blast-phase CML patient with a highly resistant, CRKP-associated tricuspid valve endocarditis, who was treated with a combination of systemic antimicrobial therapy and surgical valve repair, and subsequently underwent a successful allo-SCT. PMID:27699025

  18. Second Cancer Risk and Late Mortality in Adult Australians Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Population-Based Cohort Study.

    PubMed

    Vajdic, Claire M; Mayson, Eleni; Dodds, Anthony J; O'Brien, Tracey; Wilcox, Leonie; Nivison-Smith, Ian; Le Marsney, Renate; Daniels, Benjamin; Ashton, Lesley J

    2016-05-01

    We quantified the risk of second cancer and late mortality in a population-based Australian cohort of 3273 adult (≥15 years) allogeneic hematopoietic stem cell transplant recipients (1992 to 2007). Most recipients received nonradiation-based conditioning and a peripheral blood graft from a matched related donor. Using record linkage with death and cancer registries, 79 second cancers were identified a median of 3.5 years after transplantation. The competing-risk adjusted cumulative incidence of second cancers was 3.35% (95% CI, 2.59 to 4.24) at 10 years, and the cancer risk relative to the matched general population was 2.10 (95% CI, 1.65 to 2.56). We observed an excess risk of melanoma and lip, tongue, esophagus, and soft tissue cancers. Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source. In those alive 2 years after transplantation (n = 1463), the cumulative incidence of late mortality was 22.2% (95% CI, 19.7 to 24.9) at 10 years, and the risk of death relative to the matched general population was 13.8 (95% CI, 12.2 to 15.6). In multivariable modeling, risk of late death was reduced for females compared with males and those transplanted for chronic myeloid leukemia compared with acute myeloid leukemia; risk was increased for recipients with discordant sex donors, cGVHD, those undergoing second transplants, and disease relapse. Adults undergoing allogeneic transplantation have unique cancer and mortality risk profiles that continue to warrant prevention and surveillance activities targeted at high-risk subgroups.

  19. [Effects of myeloid antigen expression on hematopoietic reconstitution and disease prognosis in acute lymphocytic leukemia patients after allogeneic stem cell transplantation].

    PubMed

    Wang, Xiao-Ning; Liu, Hua-Sheng; Zhang, Mei

    2014-08-01

    This study was aimed to investigate the effects of myeloid antigen expression on hematopoietic reconstitution and disease prognosis in acute lymphocytic leukemia patients post-allogeneic stem cell transplantation (allo-HSCT). Clinical data of 20 patients with acute lymphocytic leukemia in Department of Hematology of the First Affiliated Hospital of Xi'an Jiaotong University from 2008 January to 2014 April were retrospectively analyzed, in which 5 cases were with myeloid antigen (My(+) ALL), while 15 patients were without myeloid antigen expression (My(-) ALL). Differences in prognosis and hematopoietic reconstitution post-allo-HSCT were observed in My(+) ALL and My(-) ALL patients. The results showed that the poor platelet engraftment in patients with My(+) ALL was found more than that in My(-)ALL patients. Three My(+) ALL patients experienced skin chronic graft versus host disease (cGVHD) including local in 2 cases and extensive in one case, and 3 My(-) ALL patients developed grade I-II acute GVHD, while five patients of My(-) ALL experienced cGVHD including local in 3 cases, extensive in 2 cases. One and two year overall survival rate of My(+) ALL and My(-) ALL patients was 80% and 85.7%, 53% and 69.8% respectively, one and two year progress-free survival rate was 53.3% and 54.7%, 26% and 27.4%, respectively. And there was no significant statistical difference between two groups (P > 0.05). It is concluded that the myeloid antigen expression may impact the platelet engraftment post-transplantation. There is no significant difference between one and two year overall survival rate and progress-free survival rate of My(+) ALL and My(-) ALL patients after allogeneic stem cell transplantation.

  20. Expansion of recipient-derived antiviral T cells may influence donor chimerism after allogeneic stem cell transplantation.

    PubMed

    Borchers, S; Weissinger, E M; Pabst, B; Ganzenmueller, T; Dammann, E; Luther, S; Diedrich, H; Ganser, A; Stadler, M

    2013-12-01

    Donor chimerism (DC) analysis is an important marker in the hematopoietic stem cell transplant follow-up. Here, we present evidence for a possible relationship of infectious complications and declines in DC. We analyzed the DC in patients experiencing cytomegalovirus (CMV) reactivation. In addition, in some patients chimerism analyses of T-cell subsets were performed. CMV-specific cytotoxic T-lymphocytes (CMV-CTL) were monitored using human leukocyte antigen-restricted multimer staining. Interestingly, CMV reactivation was accompanied by changes in DC in 11 of 67 patients transplanted. For example, DC declined in a cord blood recipient, in both total leukocytes and CD4 and CD8 T-cell subsets upon CMV reactivation. The latter was controlled after only 5 days through expanding CMV-CTL of 96% recipient origin, according to chimerism analysis of CMV-CTL (enriched beyond 50%). In another patient, transplanted after reduced-intensity conditioning from a DQB1 mismatched, CMV seronegative donor, incipient CMV reactivation was completely aborted by CMV-CTL of recipient origin. However, at the same time, mixed chimerism dropped from 51% to 0% donor type, resulting in late graft rejection. Our data indicate that chimerism analyses in subset populations lead to a better understanding of declining total leukocyte chimerism. Furthermore, recipient-derived CMV-CTL may be able to control CMV reactivation after reduced-intensity conditioning. We speculate that autologous CMV-CTL may be instrumental to overcome recurrent CMV reactivations, especially in patients transplanted from CMV-seronegative donors. In addition, the expansion of recipient-derived CMV-CTL may contribute to both, graft failure or to conversion to full DC.

  1. Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers.

    PubMed

    Thiede, C; Bornhäuser, M; Oelschlägel, U; Brendel, C; Leo, R; Daxberger, H; Mohr, B; Florek, M; Kroschinsky, F; Geissler, G; Naumann, R; Ritter, M; Prange-Krex, G; Lion, T; Neubauer, A; Ehninger, G

    2001-02-01

    Sequential analysis of chimerism after allogeneic blood stem cell transplantation (BSCT) has been shown to be predictive for graft failure and relapse. We have explored the impact of a novel approach for the quantitative determination of chimerism using a commercial PCR assay with multiplex amplification of nine STR-loci and fluorescence detection. The feasibility was studied in 121 patients transplanted from related or unrelated donors. Follow-up investigation was performed in 88 patients. Twenty-eight of these patients had received a transplantation after dose-reduced conditioning therapy. Results were compared to data obtained by FISH analysis in a subgroup of patients receiving grafts from sex-mismatched donors. The analysis was possible in all patients, the median number of informative alleles was 4 (range 1-8) compared to 7 (range 1-9) in the related and unrelated situation, respectively. A good correlation was seen in 84 samples from 14 patients analyzed in parallel with STR-PCR and FISH. Decreasing values of donor chimerism were detected prior to or concomitantly with the occurrence of graft failure and relapse of disease in all patients investigated prospectively. Using FACS-sorted material, eg peripheral blood CD34+ cells, the assay permitted the detection of residual recipient cells with high sensitivity (down to one CD34+ Kasumi cell in 40,000 normal WBC). Evaluation of the inter-laboratory reproducibility revealed that in 20 samples analyzed in three different centers, the median coefficient of variation was 2.1% (range 0.7-9.6%). Taken together, the results support the use of the test as a valuable tool in the follow-up of patients undergoing allogeneic BSCT. In cases lacking PCR-detectable disease-specific gene products, this assay may represent an alternative to recently established real-time PCR methods. PMID:11236950

  2. Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Société Française de Greffe de moelle (SFGM).

    PubMed

    Michallet, M; Tanguy, M L; Socié, G; Thiébaut, A; Belhabri, A; Milpied, N; Reiffers, J; Kuentz, M; Cahn, J Y; Blaise, D; Demeocq, F; Jouet, J P; Michallet, A S; Ifrah, N; Vilmer, E; Molina, L; Michel, G; Lioure, B; Cavazzana-Calvo, M; Pico, J L; Sadoun, A; Guyotat, D; Attal, M; Curé, H; Bordigoni, P; Sutton, L; Buzyn-Veil, A; Tilly, M; Keoirruer, N; Feguex, N

    2000-02-01

    Although recurrent malignancy is the most frequent indication for second stem cell transplantation (2nd SCT), there are few reports that include sufficiently large numbers of patients to enable prognostic factor analysis. This retrospective study includes 150 patients who underwent a 2nd SCT for relapsed acute myeloblastic leukaemia (n = 61), acute lymphoblastic leukaemia (n = 47) or chronic myeloid leukaemia (n = 42) after a first allogeneic transplant (including 26 T-cell-depleted). The median interval between the first transplant and relapse, and between relapse and second transplant was 17 months and 5 months respectively. After the 2nd SCT, engraftment occurred in 93% of cases, 32% of patients developed acute graft-vs.-host disease (GVHD) >/= grade II and 38% chronic GVHD. The 5-year overall and disease-free survival were 32 +/- 8% and 30 +/- 8%, respectively, with a risk of relapse of 44 +/- 12% and a transplant-related mortality of 45 +/- 9%. In a multivariate analysis, five factors were associated with a better outcome after 2nd SCT: age < 16 years at second transplant; relapse occurring more than 12 months after the first transplant; transplantation from a female donor; absence of acute GVHD; and the occurrence of chronic GVHD. The best candidates for a second transplant are likely to be patients with acute leukaemia in remission before transplant, in whom the HLA-identical donor was female and who relapsed more than 1 year after the first transplant.

  3. Severe fludarabine neurotoxicity after reduced intensity conditioning regimen to allogeneic hematopoietic stem cell transplantation: a case report

    PubMed Central

    Annaloro, Claudio; Costa, Antonella; Fracchiolla, Nicola S; Mometto, Gabriella; Artuso, Silvia; Saporiti, Giorgia; Tagliaferri, Elena; Grifoni, Federica; Onida, Francesco; Cortelezzi, Agostino

    2015-01-01

    Key Clinical Message We present a case of severe, irreversible neurotoxicity in a 55-year-old-patient with myelofibrosis undergoing hematopoietic stem cell transplantation following a reduced intensity conditioning including fludarabine. The patient developed progressive sensory-motor, visual and consciousness disturbances, eventually leading to death. MRI imaging pattern was unique and attributable to fludarabine neurotoxicity. PMID:26273463

  4. Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry.

    PubMed

    Greinix, Hildegard T; Nachbaur, David; Krieger, Otto; Eibl, Margit; Knöbl, Paul; Kalhs, Peter; Lutz, Dieter; Linkesch, Werner; Niederwieser, Dietger; Hinterberger, Wolfgang; Lechner, Klaus; Rosenmayr, Agathe; Gritsch, Beate

    2002-06-01

    Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined. PMID:12060131

  5. Non-myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Relapsed and Refractory Mantle Cell Lymphoma: A Single Center Analysis in the Rituximab Era

    PubMed Central

    Mussetti, Alberto; Devlin, Sean M.; Castro-Malaspina, Hugo R; Barker, Juliet N.; Giralt, Sergio A.; Zelenetz, Andrew D.

    2015-01-01

    Relapsed and refractory (rel/ref) mantle cell lymphoma (MCL) portends a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative therapy in this setting. We analyzed survival outcomes of 29 recipients of non-myeloablative allo-HSCT for rel/ref MCL, and studied possible prognostic factors in this setting. The cumulative incidence of disease progression and non-relapse mortality at 3 years were 28% (95% confidence interval [CI]: 13-46%) and 29% (95%CI: 13-47%), respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at days +100 and +180 were 34% (95%CI: 18-52%) and 45% (95%CI: 26-62%), respectively. With a median follow-up in survivors of 53 (range 24-83) months, the 3-year overall survival (OS) and progression-free survival (PFS) were 54% (95%CI: 38-76%) and 41% (95%CI: 26-64%), respectively. In vivo T-cell depletion with alemtuzumab (n=6) was associated with inferior 3-year PFS (0% vs. 51%, p=0.007) and OS (17% vs. 64%, p=0.014). Conversely, a second line international prognostic index (sIPI) at transplantation equal to 0 (no risk factors) was associated with an improved 3-year PFS (52% vs. 22%, p=0.020) and OS (71% vs. 22%, p=0.006) compared to sIPI ≥1. Performing an allo-HSCT before 2007 was associated with a decreased 3-year OS (25% vs. 76%, p=0.015) but not with a significantly inferior PFS (17% vs. 59%, p=0.058). In this single center series, we report encouraging results with allo-HSCT for patients with rel/ref MCL. High alemtuzumab doses should probably be avoided in this context. PMID:26146802

  6. A Prospective Study of an Alemtuzumab Containing Reduced-intensity Allogeneic Stem Cell Transplantation Program in Patients with Poor-Risk and Advanced Lymphoid Malignancies

    PubMed Central

    Sauter, Craig S.; Chou, Joanne F.; Papadopoulos, Esperanza B.; Perales, Miguel-Angel; Jakubowski, Ann A.; Young, James W.; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2015-01-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight advanced lymphoma patients underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporin-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years is 25% (95% CI: 13-40) and 44% (95% CI: 28-59%) respectively. Previous high-dose therapy and autologous stem cell transplantation (HDT-ASCT) and elevated LDH at the time of allo-SCT resulted in inferior OS. Within this cohort of high-risk lymphoma patients, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of POD, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT. PMID:24528216

  7. A prospective study of an alemtuzumab containing reduced-intensity allogeneic stem cell transplant program in patients with poor-risk and advanced lymphoid malignancies.

    PubMed

    Sauter, Craig S; Chou, Joanne F; Papadopoulos, Esperanza B; Perales, Miguel-Angel; Jakubowski, Ann A; Young, James W; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2014-12-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplant (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight patients with advanced lymphoma underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporine-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years was 25% (95% confidence interval [CI]: 13-40%) and 44% (95% CI: 28-59%), respectively. Previous high-dose therapy and autologous stem cell transplant (HDT-ASCT) and elevated lactate dehydrogenase (LDH) at the time of allo-SCT resulted in inferior OS. Within this cohort of patients with high-risk lymphoma, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of progression of disease, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT.

  8. Safety and efficacy of total body irradiation, cyclophosphamide, and cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia.

    PubMed

    Mori, Takehiko; Aisa, Yoshinobu; Kato, Jun; Yamane, Akiko; Nakazato, Tomonori; Shigematsu, Naoyuki; Okamoto, Shinichiro

    2012-04-01

    Disease relapse still greatly interferes with the success of allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). This study retrospectively evaluated the long-term safety and efficacy of a conditioning regimen consisting of total body irradiation (TBI; 12 Gy), cyclophosphamide (CY; 60 mg kg(-1) , two doses), and high-dose cytarabine (Ara-C; 2 g m(-2) ; four doses) for patients with ALL. Fifty-five patients (median age: 31-years old) were evaluated. Stem cells were from human leukocyte antigen-identical siblings in 22 patients and from alternative donors in 33. There were no cases of early death before engraftment, and 100-day transplant-related mortality was 7.3%. With a median follow-up period of 9.6 years, 5-year overall and disease-free survival were 63.2% (95% CI: 46.5-79.9%) and 63.6% (95% CI: 47.1-80.1%) in patients with complete remission, respectively, both of which were significantly higher than the values of 27.3% (95% CI: 8.7-46.0%) and 22.7% (95% CI: 5.3-40.1%) for patients in advanced stages (P < 0.01). These results suggest that TBI and CY (TBI-CY) plus Ara-C could be a feasible and effective conditioning regimen for adult patients with ALL both in remission and in advanced stages, and a future study to compare this combination therapy with TBI-CY is required.

  9. Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

    PubMed

    Brissot, Eolia; Cahu, Xavier; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Peterlin, Pierre; Le Bourgeois, Amandine; Harousseau, Jean-Luc; Milpied, Noel; Bene, Marie-Christine; Moreau, Philippe; Mohty, Mohamad; Chevallier, Patrice

    2015-04-01

    In the myeloablative transplant setting, the early use of fluconazole prophylaxis provides a benefit in overall survival. Recent changes in transplantation practices, including the use of peripheral blood stem cells (PBSC) and/or reduced intensity conditioning (RIC) regimen may have favorably impacted the epidemiology of invasive fungal infections (IFI) after allogeneic stem cell transplantation (allo-SCT). Yet, the impact of removing fluconazole prophylaxis after RIC PBSC allotransplant is ill known. Here, a retrospective analysis was performed comparing patients who received fluconazole as antifungal prophylaxis (n = 53) or not (n = 56) after allo-SCT for acute leukemia or myelodysplastic/myeloproliferative syndrome. Sixteen IFI were documented (14 %) at a median time of 103 days after transplantation, including eight before day +100, at a similar rate, whether the patients received fluconazole prophylaxis (13 %) or not (16 %). IFI were due mainly to Aspergillus species (87 %), and only two Candida-related IFI (13 %) were documented in the non-fluconazole group before day +100. The incidences of IFI (overall, before or after day +100) as well as 3-year overall and disease-free survival, non-relapse mortality, or acute and chronic graft-versus-host disease (GVHD) were similar between both groups. In conclusion, this study suggests that fluconazole may not be required at the initial phase of RIC allo-SCT using PBSC. This result has to be confirmed prospectively while Aspergillus prophylaxis should be discussed in this particular setting.

  10. The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation.

    PubMed

    Heidegger, Simon; van den Brink, Marcel R M; Haas, Tobias; Poeck, Hendrik

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs) such as toll-like receptors (TLR) and nod-like receptors (NLR) are critically involved in the pathogenesis of acute GVHD. Currently, a widely accepted model postulates that intensive chemotherapy and/or total-body irradiation during pre-transplant conditioning results in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells to trigger the production of pro-inflammatory cytokines (cytokine storm) that modulate T cell allo-reactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL) effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms that govern GVHD versus GVL is urgently needed. This may ultimately allow to design modulators, which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT.

  11. Haploidentical transplantation. Importance of histocompatibility testing and chimerism studies in allogeneic bone marrow/stem cell transplantation.

    PubMed

    Rebellato, L M; Dobbs, L J

    2001-01-01

    The transplantation of hematopoietic stem cells is sometimes the only treatment option for certain types of malignancies and hematological disorders. The best way to ensure a positive outcome from this type of procedure is to secure an identical human lymphocyte antigen-matched donor or use an autologous graft. This article reviews the indications for transplantation, the recipient and donor selection process, and posttransplant follow-up. The advantages of using haploidentical donors and the typing process also will be discussed.

  12. A phase I study of CD25/regulatory T-cell-depleted donor lymphocyte infusion for relapse after allogeneic stem cell transplantation

    PubMed Central

    Nikiforow, Sarah; Kim, Haesook T.; Daley, Heather; Reynolds, Carol; Jones, Kyle Thomas; Armand, Philippe; Ho, Vincent T.; Alyea, Edwin P.; Cutler, Corey S.; Ritz, Jerome; Antin, Joseph H.; Soiffer, Robert J.; Koreth, John

    2016-01-01

    Donor lymphocyte infusions are used to treat relapse after allogeneic hematopoietic stem cell transplantation, but responses are inadequate. In addition to effector cells, infusions contain CD25+ regulatory T cells (Treg) that may suppress graft-versus-tumor responses. We undertook a phase I study of donor lymphocyte infusions depleted of CD25+ T cells in patients with hematologic malignancies who had relapsed after transplantation. Twenty-one subjects received CD25/Treg-depleted infusions following removal of CD25+ cells using antibody-conjugated magnetic beads. Sixteen subjects received prior cytoreductive therapy. Four were in complete remission at the time of infusion. Two dose levels were administered: 1×107 (n=6) and 3×107 CD3+ cells/kg (n=15). A median 2.3 log-depletion of CD4+CD25+FOXP3+ Treg was achieved. Seven subjects (33%) developed clinically significant graft-versus-host disease by 1 year, including one patient who died. At dose level 1, five subjects had progressive disease and one had stable disease. At dose level 2, nine subjects (60%) achieved or maintained responses (8 complete responses, 1 partial response), including seven with active disease at the time of infusion. A shorter period between relapse and infusion was associated with response at dose level 2 (P=0.016). The 1-year survival rate was 53% among patients treated with dose level 2. Four of eight subjects with acute myeloid leukemia remained in remission at 1 year. When compared to unmodified donor lymphocyte infusions in 14 contemporaneous patients meeting study eligibility, CD25/Treg depletion was associated with a better response rate and improved event-free survival. Circulating naïve and central memory CD4+ T cells increased after CD25/Treg-depleted infusion, but no immunophenotypic signature for response was noted. CD25/Treg-depleted donor infusion appears feasible and capable of inducing graft-versus-tumor responses without excessive graft-versus-host disease. (Clinical

  13. Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome

    PubMed Central

    Reikvam, Håkon; Grønningsæter, Ida-Sofie; Ahmed, Aymen Bushra; Hatfield, Kimberley; Bruserud, Øystein

    2015-01-01

    Allogeneic stem cell transplantation is commonly used in the treatment of younger patients with severe hematological diseases, and endothelial cells seem to be important for the development of several posttransplant complications. Capillary leak syndrome is a common early posttransplant complication where endothelial cell dysfunction probably contributes to the pathogenesis. In the present study we investigated whether the pretreatment serum metabolic profile reflects a risk of posttransplant capillary leak syndrome. We investigated the pretransplant serum levels of 766 metabolites for 80 consecutive allotransplant recipients. Patients with later capillary leak syndrome showed increased pretherapy levels of metabolites associated with endothelial dysfunction (homocitrulline, adenosine) altered renal regulation of fluid and/or electrolyte balance (betaine, methoxytyramine, and taurine) and altered vascular function (cytidine, adenosine, and methoxytyramine). Additional bioinformatical analyses showed that capillary leak syndrome was also associated with altered purine/pyrimidine metabolism (i.e., metabolites involved in vascular regulation and endothelial functions), aminoglycosylation (possibly important for endothelial cell functions), and eicosanoid metabolism (also involved in vascular regulation). Our observations are consistent with the hypothesis that the pretransplant metabolic status can be a marker for posttransplant abnormal fluid and/or electrolyte balance. PMID:26609191

  14. Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies.

    PubMed

    Yerushalmi, R; Shem-Tov, N; Danylesko, I; Avigdor, A; Nagler, A; Shimoni, A

    2015-12-01

    Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non-relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease. PMID:26237166

  15. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial.

    PubMed

    Middeke, J M; Herbst, R; Parmentier, S; Bug, G; Hänel, M; Stuhler, G; Schäfer-Eckart, K; Rösler, W; Klein, S; Bethge, W; Bitz, U; Büttner, B; Knoth, H; Alakel, N; Schaich, M; Morgner, A; Kramer, M; Sockel, K; von Bonin, M; Stölzel, F; Platzbecker, U; Röllig, C; Thiede, C; Ehninger, G; Bornhäuser, M; Schetelig, J

    2016-02-01

    In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML. PMID:26283567

  16. Interferon-α: A Potentially Effective Treatment for Minimal Residual Disease in Acute Leukemia/Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2015-11-01

    In this prospective clinical study, the safety and efficacy of preemptive interferon-α (IFN-α) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n = 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-α. A total of 22 patients received preemptive IFN-α; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-α group and 62.9% for the DLI group (P < .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-α group and 35.6% for the DLI group (P = .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-α group and 4.4% for the DLI group (P = .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-α group and 60.0% for the DLI group (P = .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly associated with poorer clinical outcomes. Thus, preemptive IFN-α may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT.

  17. Stem Cells

    MedlinePlus

    Stem cells are cells with the potential to develop into many different types of cells in the body. They serve as a repair ... body. There are two main types of stem cells: embryonic stem cells and adult stem cells. Stem ...

  18. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

    PubMed

    Vendramin, Antonio; Gimondi, Silvia; Bermema, Anisa; Longoni, Paolo; Rizzitano, Sara; Corradini, Paolo; Carniti, Cristiana

    2014-12-01

    Myeloid-derived suppressor cells (MDSCs) are powerful immunomodulatory cells that in mice play a role in infectious and inflammatory disorders, including acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Their relevance in clinical acute GVHD is poorly known. We analyzed whether granulocyte colony-stimulating factor (G-CSF) administration, used to mobilize hematopoietic stem cells, affected the frequency of MDSCs in the peripheral blood stem cell grafts of 60 unrelated donors. In addition, we evaluated whether the MDSC content in the peripheral blood stem cell grafts affected the occurrence of acute GVHD in patients undergoing unrelated donor allogeneic stem cell transplantation. Systemic treatment with G-CSF induces an expansion of myeloid cells displaying the phenotype of monocytic MDSCs (Lin(low/neg)HLA-DR(-)CD11b(+)CD33(+)CD14(+)) with the ability to suppress alloreactive T cells in vitro, therefore meeting the definition of MDSCs. Monocytic MDSC dose was the only graft parameter to predict acute GVHD. The cumulative incidence of acute GVHD at 180 days after transplantation for recipients receiving monocytic MDSC doses below and above the median was 63% and 22%, respectively (P = .02). The number of monocytic MDSCs infused did not impact the relapse rate or the transplant-related mortality rate (P > .05). Although further prospective studies involving larger sample size are needed to validate the exact monocytic MDSC graft dose that protects from acute GVHD, our results strongly suggest the modulation of G-CSF might be used to affect monocytic MDSCs graft cell doses for prevention of acute GVHD.

  19. A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates

    PubMed Central

    Hu, Xinyang; Xu, Yinchuan; Zhong, Zhiwei; Wu, Yan; Zhao, Jing; Wang, Yingchao; Cheng, Haifeng; Kong, Minjian; Zhang, Fengjiang; Chen, Qi; Sun, Jianzhong; Li, Qian; Jin, Jing; Li, Qingju; Chen, Lihong; Wang, Chen; Zhan, Hongwei; Fan, Youqi; Yang, Qian; Yu, Lei; Wu, Rongrong; Liang, Jie; Zhu, Jinyun; Wang, Ya; Jin, Yiping; Lin, Yifan; Yang, Fan; Jia, Liangliang; Zhu, Wei; Chen, Jinghai; Yu, Hong

    2016-01-01

    Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell–based myocardial therapy are needed. Objective: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. Methods and Results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×107 cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells–treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. Conclusions: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted. PMID:26838793

  20. Immunosuppression of Allogenic Mesenchymal Stem Cells Transplantation after Spinal Cord Injury Improves Graft Survival and Beneficial Outcomes

    PubMed Central

    Torres-Espín, Abel; Redondo-Castro, Elena; Hernandez, Joaquim

    2015-01-01

    Abstract Cell therapy for spinal cord injury (SCI) is a promising strategy for clinical application. Mesenchymal stem cells (MSC) have demonstrated beneficial effects following transplantation in animal models of SCI. However, despite the immunoprivilege properties of the MSC, their survival in the injured spinal cord is reduced due to the detrimental milieu in the damaged tissue and immune rejection of the cells. The limited survival of the engrafted cells may determine the therapy success. Therefore, we compared two strategies to increase the presence of the cells in the injured spinal cord in rats: increasing the amount of MSC transplants and using immunosuppressive treatment with FK506 after transplantation. Functional outcomes for locomotion and electrophysiological responses were assessed. The grafted cells survival and the amount of cavity and spared tissue were studied. The findings indicate that immunosuppression improved grafted cells survival. A cell–dose effect was found regarding locomotion recovery and tissue protection independent of immunosuppression. Nevertheless, immunosuppression enhanced the electrophysiological outcomes and allowed filling of the cavity formed after injury by new regenerative tissue and axons. These results indicate that MSC transplantation combined with immunosuppression prolongs the survival of engrafted cells and improves functional and morphological outcomes after SCI. PMID:25203134

  1. KIR genotypic diversity in Portuguese and analysis of KIR gene allocation after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Ligeiro, D; Buhler, S; Abecasis, M; Abade, O; Sanchez-Mazas, A; da Silva, M Gomes; Trindade, H

    2016-05-01

    The diversity of killer-cell immunoglobulin-like receptors (KIR) genes was evaluated in Portuguese and the observed genotypic profiles were found related to the ones reported in European populations. The KIR repertoire after hematopoietic stem cell transplantation is determined by these gene frequencies and the KIR group B motifs are the less common. We estimated donor-KIR/recipient-ligand interactions in transplants with related donors and unrelated donors found in a local registry or from abroad. A large fraction of transplants had all three ligands of inhibitory receptors, and therefore, in theory were not prone to natural killer cell (NK) mediated alloreactivity. Furthermore, the distribution of KIR alloreactive interactions was found independent of the donor-recipient genetic proximity, probably because of different gene segregation and comparable KIR frequencies in the donor pools. PMID:27075774

  2. Risk Factors, Pattern and Clinical Outcome of Acute Graft Versus Host Disease in Acute Leukemia Patients Undergoing Allogeneic Stem Cell Transplant.

    PubMed

    Gupta, Alok; Punatar, Sachin; Gawande, Jayant; Mathew, Libin; Bagal, Bhausaheb; Kannan, Sadhana; Khattry, Navin

    2015-12-01

    We sought to determine risk factors, pattern and outcome of acute graft versus host disease (aGVHD) in seventy-seven acute leukemia patients who underwent allogeneic stem cell transplant at our centre from January 2008 to March 2013. GVHD prophylaxis with cyclosporine-methotrexate or cyclosporine-mycophenolate mofetil was used. Patients were divided in 2 groups, grade II-IV aGVHD (group A) and grade 0-I aGVHD (group B). Incidence of any grade and grade II-IV aGVHD was 44 and 18 %, respectively. The most common site of aGVHD was gastro-intestinal tract (65 %) followed by skin (35 %). Higher total nucleated cell (TNC) dose infused was associated with increased incidence of grade II-IV aGVHD. Incidence of relapse and incidence of slippage of chimerism was 21 and 36 % in group A while 37 and 27 % in group B respectively. Transplant related mortality (TRM) was 21 % in group A and 13 % in group B. Probability of OS and RFS at 4 years was 63 and 34 % in group A compared with 40 and 38 % in group B, respectively. We conclude that higher TNC dose infused is a risk factor for grade II-IV aGVHD with gut being the commonest site. Grade II-IV aGVHD did not have a significant impact on incidence of relapse, TRM and OS.

  3. Health-related quality of life in pediatric patients after allogeneic SCT: development of the PedsQL Stem Cell Transplant module and results of a pilot study.

    PubMed

    Lawitschka, A; Güclü, E D; Varni, J W; Putz, M; Wolff, D; Pavletic, S; Greinix, H; Peters, C; Felder-Puig, R

    2014-08-01

    With increased survival after pediatric allogeneic hematopoietic SCT health-related quality of life (HRQL) has emerged as an essential health outcome. The impact of transplant and chronic GVHD (cGVHD)-associated morbidity remains a major obstacle. In 2005, the National Institutes of Health (NIH) Consensus Conference on Criteria for Clinical Trials in cGVHD recommended HRQL tools as an independent measure of the impact of disease burden. The NIH recommendations did not provide a cGVHD-specific tool for HRQOL measures in children. This report focuses on the development of an SCT-specific instrument to assess HRQL in children and adolescents. For the assessment of generic HRQL we chose the PedsQL (Pediatric Quality of Life Inventory) Generic Cores Scales, which have been used in a large number of healthy, acutely ill and chronically ill children and adolescents. To capture SCT- and, specifically, cGVHD-related problems, we developed the PedsQL Stem Cell Transplant module by reviewing the literature, taking over some items/scales of other PedsQL modules, interviewing patients, parents and members of the health-care team, and applying the PedsQL measurement methods. The final PedsQL Stem Cell Transplant module consists of the HRQL domains: pain and hurt, fatigue/sleeping problems/weakness, nausea, worry/anxiety about disease/treatment, nutritional problems, neurocognitive problems, communication about disease/treatment, loneliness, physical functioning and additional somatic complaints (pruritus, skin inflammation, oral problems, eyes or breathing) including patients' and parents' assessment. It was tested in 35 pediatric patients, who were referred to our SCT Outpatient Clinic about 100 days post SCT. Both the generic PedsQL and the SCT-specific scales showed high internal consistency, with Cronbach alpha levels of ⩾0.70 in almost all scales. Most problems were detected within the HRQL domains of physical functioning and pain. The summary scores of the generic Peds

  4. Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Fuji, Shigeo; Kim, Sung-Won; Fukuda, Takahiro; Mori, Shin-ichiro; Yamasaki, Satoshi; Morita-Hoshi, Yuriko; Ohara-Waki, Fusako; Heike, Yuji; Tobinai, Kensei; Tanosaki, Ryuji; Takaue, Yoichi

    2008-05-01

    In a mouse model, inflammatory cytokines play a primary role in the development of acute graft-versus-host disease (aGVHD). Here, we retrospectively evaluated whether the preengraftment C-reactive protein (CRP) value, which is used as a surrogate marker of inflammation, could predict posttransplant complications including GVHD. Two hundred twenty-four adult patients (median age, 47 years; range: 18-68 years) underwent conventional stem cell transplantation (CST, n = 105) or reduced-intensity stem cell transplantation (RIST, n = 119). Patients were categorized according to the maximum CRP value during neutropenia: the "low-CRP" group (CRP < 15 mg/dL, n = 157) and the "high-CRP" group (CRP >or= 15 mg/dL, n = 67). The incidence of documented infections during neutropenia was higher in the high-CRP group (34% versus 17%, P = .004). When patients with proven infections were excluded, the CRP value was significantly lower after RIST than after CST (P = .017) or after related than after unrelated transplantation (P < .001). A multivariate analysis showed that male sex, unrelated donor, and HLA-mismatched donor were associated with high CRP values. The high-CRP group developed significantly more grade II-IV aGVHD (P = .01) and nonrelapse mortality (NRM) (P < .001), but less relapse (P = .02). The present findings suggest that the CRP value may reflect the net degree of tissue damage because of the conditioning regimen, infection, and allogeneic immune reactions, all of which lead to subsequent aGVHD and NRM.

  5. The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Michonneau, David; Sagoo, Pervinder; Breart, Béatrice; Garcia, Zacarias; Celli, Susanna; Bousso, Philippe

    2016-01-19

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a curative treatment for hematologic malignancies, relies on donor cytotoxic T lymphocyte (CTL)-mediated graft-versus-leukemia (GVL) effect. Major complications of HSCT are graft-versus-host disease (GVHD) that targets specific tissues and tumor relapses. However, the mechanisms dictating the anatomical features of GVHD and GVL remain unclear. Here, we show that after HSCT, CTLs exhibited different killing activity in distinct tissues, being highest in the liver and lowest in lymph nodes. Differences were imposed by the microenvironment, partly through differential PD-1 ligand expression, which was strongly elevated in lymph nodes. Two-photon imaging revealed that PD-1 blockade restored CTL sensitivity to antigen and killing in lymph nodes. Weak CTL activity in lymph nodes promoted local tumor escape but could be reversed by anti-PD-1 treatment. Our results uncover a mechanism generating an anatomical segregation of CTL activity that might dictate sites of GVHD and create niches for tumor escape. PMID:26795248

  6. Dermoscopic Follow-Up of the Skin towards Acute Graft-versus-Host-Disease in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Kaminska-Winciorek, Grazyna; Czerw, Tomasz; Kruzel, Tomasz; Giebel, Sebastian

    2016-01-01

    Background. Acute graft-versus-host disease (aGVHD) involving skin is one of the most frequent complications of allogeneic hematopoietic stem cell transplantation (alloHSCT), usually diagnosed based on clinical manifestations. So far, skin biopsy with histopathological evaluation is the only method to confirm the diagnosis. Objective. In this prospective study we monitored alloHSCT recipients by dermoscopy in order to assess its utility as an alternative noninvasive tool to early diagnose acute GVHD. Methods. Thirteen consecutive patients who received alloHSCT were examined clinically and dermoscopically towards aGVHD [days 28 (±7), 56 (±7), and 100 (±7)], as well as in each patient who developed cutaneous aGVHD diagnosed according to clinical criteria (Glucksberg scale). Results. Six patients (46%) developed symptoms of cutaneous acute GVHD (grade 1, n = 3; grade 2, n = 3). Dermoscopic evaluation revealed pinkish or reddish background and well-visible, multiple thin telangiectasias. Conclusion. To our knowledge, this is the first report on the use of dermoscopy to evaluate skin involvement in the course of acute GVHD suggesting its role as a diagnostic tool in follow-up of GVHD, which can be also used before clinical symptoms occur. PMID:27446950

  7. Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King's College Hospital.

    PubMed

    Wang, Meng; Wang, Wenjia; Abeywardane, Ayesha; Adikarama, Malinthi; McLornan, Donal; Raj, Kavita; de Lavallade, Hugues; Devereux, Stephen; Mufti, Ghulam J; Pagliuca, Antonio; Potter, Victoria T; Mijovic, Aleksandar

    2015-01-01

    Autoimmune hemolytic anemia (AIHA) is a recognized complication of hematopoietic stem cell transplantation (HSCT); it is often refractory to treatment and carries a high mortality. To improve understanding of the incidence, risk factors, and clinical outcome of post-transplantation AIHA, we analyzed 533 patients who received allogeneic HSCT, and we identified 19 cases of AIHA after HSCT (overall incidence, 3.6%). The median time to onset, from HSCT to AIHA, was 202 days. AIHA was associated with HSCT from unrelated donors (hazard ratio [HR], 5.28; 95% confidence interval [CI], 1.22 to 22.9; P = .026). In the majority (14 of 19; 74%) of AIHA patients, multiple agents for treatment were required, with only 9 of 19 (47%) patients achieving complete resolution of AIHA. Patients with post-transplantation AIHA had a higher overall mortality (HR, 2.48; 95% CI, 1.33 to 4.63; P = .004), with 36% (4 of 11 cases) of deaths attributable to AIHA. PMID:25262883

  8. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma.

    PubMed

    Kröger, Nicolaus; Shimoni, Avichai; Zagrivnaja, Maria; Ayuk, Francis; Lioznov, Michael; Schieder, Heike; Renges, Helmut; Fehse, Boris; Zabelina, Tatjana; Nagler, Arnon; Zander, Axel R

    2004-11-15

    To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease.

  9. Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis.

    PubMed

    Kröger, Nicolaus; Zabelina, Tatjana; Schieder, Heike; Panse, Jens; Ayuk, Francis; Stute, Norbert; Fehse, Natalja; Waschke, Olga; Fehse, Boris; Kvasnicka, Hans Michael; Thiele, Jürgen; Zander, Axel

    2005-03-01

    A prospective pilot study was performed to evaluate the effect of reduced-intensity conditioning with busulphan (10 mg/kg), fludarabine (180 mg/qm) and anti-thymocyte globulin followed by allogeneic stem cell transplantation from related (n = 8) and unrelated donors (n = 13) in 21 patients with myelofibrosis. The median age of the patients was 53 years (range, 32-63). No primary graft failure occurred. The median time until leucocyte (>1.0 x 10(9)/l) and platelet (>20 x 10(9)/l) engraftment was 16 (range, 11-26) and 23 d (range, 9-139) respectively. Complete donor chimaerism on day 100 was seen in 20 patients (95%). Acute graft-versus-host disease (GvHD) grades II-IV and III/IV occurred in 48% and 19% of cases and 55% of the patients had chronic GvHD. Treatment-related mortality was 0% at day 100 and 16% [95% confidence interval (CI): 0-32%] at 1 year. Haematological response was seen in 100% and complete histopathological remission was observed in 75% of the patients and 25% of the patients showed partial histopathological remission with a continuing decline in the grade of fibrosis. After a median follow-up of 22 months (range, 4-59), the 3-year estimated overall and disease-free survival was 84% (95% CI: 67-100%).

  10. Risk Factors for Steroid-Refractory Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation from Matched Related or Unrelated Donors.

    PubMed

    Calmettes, Claire; Vigouroux, Stéphane; Labopin, Myriam; Tabrizi, Reza; Turlure, Pascal; Lafarge, Xavier; Marit, Gérald; Pigneux, Arnaud; Leguay, Thibaut; Bouabdallah, Krimo; Dilhuydy, Marie-Sarah; Duclos, Cédric; Mohr, Catherine; Lascaux, Axelle; Dumas, Pierre-Yves; Dimicoli-Salazar, Sophie; Saint-Lézer, Arnaud; Milpied, Noël

    2015-05-01

    We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients.

  11. Donor Nucleotide-Binding Oligomerization-Containing Protein 2 (NOD2) Single Nucleotide Polymorphism 13 Is Associated with Septic Shock after Allogeneic Stem Cell Transplantation.

    PubMed

    Grube, Matthias; Brenmoehl, Julia; Rogler, Gerhard; Hahn, Joachim; Herr, Wolfgang; Holler, Ernst

    2015-08-01

    Single nucleotide polymorphisms (SNPs) within nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor (TLR) 5 genes have been recently associated with the incidence and outcome of infections. In this study, we analyzed 38 patients with septic shock after allogeneic stem cell transplantation (allo-SCT) for an association of SNPs within NOD2 and TLR5 genes, with susceptibility to septic shock. One hundred twenty-seven transplant recipients unaffected by any infectious complications were used as controls. We found a significant association between the presence of donor NOD2 SNP13 (3016_3017insC) and the incidence of septic shock (P = .002). In multivariate analysis, donor NOD2 SNP13 appeared as an independent risk factor for the incidence of septic shock after allo-SCT. No association was found for recipient SNPs (NOD2 and TLR5) and donor NOD2 SNP8, SNP12, and TLR5-Stop SNP. Our results suggest that NOD2 SNP13 has an impact on the pathophysiology of severe infectious complications and is an independent risk factor for the development of septic shock after allo-SCT.

  12. Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King's College Hospital.

    PubMed

    Wang, Meng; Wang, Wenjia; Abeywardane, Ayesha; Adikarama, Malinthi; McLornan, Donal; Raj, Kavita; de Lavallade, Hugues; Devereux, Stephen; Mufti, Ghulam J; Pagliuca, Antonio; Potter, Victoria T; Mijovic, Aleksandar

    2015-01-01

    Autoimmune hemolytic anemia (AIHA) is a recognized complication of hematopoietic stem cell transplantation (HSCT); it is often refractory to treatment and carries a high mortality. To improve understanding of the incidence, risk factors, and clinical outcome of post-transplantation AIHA, we analyzed 533 patients who received allogeneic HSCT, and we identified 19 cases of AIHA after HSCT (overall incidence, 3.6%). The median time to onset, from HSCT to AIHA, was 202 days. AIHA was associated with HSCT from unrelated donors (hazard ratio [HR], 5.28; 95% confidence interval [CI], 1.22 to 22.9; P = .026). In the majority (14 of 19; 74%) of AIHA patients, multiple agents for treatment were required, with only 9 of 19 (47%) patients achieving complete resolution of AIHA. Patients with post-transplantation AIHA had a higher overall mortality (HR, 2.48; 95% CI, 1.33 to 4.63; P = .004), with 36% (4 of 11 cases) of deaths attributable to AIHA.

  13. Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression-Free Survival for Patients with Chronic Myelomonocytic Leukemia.

    PubMed

    Kongtim, Piyanuch; Popat, Uday; Jimenez, Antonio; Gaballa, Sameh; El Fakih, Riad; Rondon, Gabriela; Chen, Julianne; Bueso-Ramos, Carlos; Borthakur, Gautam; Pemmaraju, Naveen; Garcia-Manero, Guillermo; Kantarjian, Hagop; Alousi, Amin; Hosing, Chitra; Anderlini, Paolo; Khouri, Issa F; Kebriaei, Partow; Andersson, Borje S; Oran, Betul; Rezvani, Katayoun; Marin, David; Shpall, Elizabeth J; Champlin, Richard E; Ciurea, Stefan O

    2016-01-01

    The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant (allo-SCT) at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival (PFS). The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P = .03), whereas treatment-related mortality at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; P = .84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; P = .04). Our data support the use of hypomethylating agents before allo-SCT for patients with CMML to achieve morphologic remission and improve PFS of these patients. Future studies are needed to confirm these findings.

  14. JAK2 p.V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse

    PubMed Central

    Lange, Thoralf; Edelmann, Anja; Siebolts, Udo; Krahl, Rainer; Nehring, Claudia; Jäkel, Nadja; Cross, Michael; Maier, Jacqueline; Niederwieser, Dietger; Wickenhauser, Claudia

    2013-01-01

    The risk profile and prognosis of patients with myelofibrosis is well described by the Dynamic International Prognostic Scoring System risk categorization. Allogeneic stem cell transplantation is considered for intermediate-2/high risk disease. However, indicators of prognosis after transplantation are still lacking. Seventy simultaneously collected pairs of trephine and blood samples were quantified for JAK2 p.V617F allele burden to compare test sensitivity. The course of 30 patients with JAK2 p.V617F-positive myeloproliferative neoplasia was correlated with allele burden after transplantation. Monitoring can be performed on full blood samples as well as trephine biopsies, provided that techniques with ample sensitivity (0.01% to 0.001%) are available. Measurement of allele burden on day 28 after transplantation discriminates two prognostic groups: patients with a JAK2 p.V617F allele burden >1% have a significantly higher risk of relapse of JAK2 p.V617F positive neoplasia (P=0.04) and a poorer overall survival (P<0.01). In conclusion, measurement of JAK2 p.V617F allele burden early after transplantation is an important predictive parameter in monitoring patients following this treatment. As this might provide an important tool in early management of imminent early relapse it will be important to define consensus guidelines for optimal monitoring. PMID:23300178

  15. Allogeneic stem cell transplantation in chronic lymphocytic leukemia patients with 17p deletion: consult-transplant v consult-no-transplant analysis

    PubMed Central

    Poon, Michelle L.; Fox, Patricia S.; Samuels, Barry I.; O’Brien, Susan; Jabbour, Elias; Hsu, Yvonne; Gulbis, Alison; Korbling, Martin; Champlin, Richard; Abruzzo, Lynne V.; Bassett, Roland L.; Khouri, Issa F.

    2015-01-01

    Allogeneic stem cell transplantation (alloSCT) can overcome the adverse prognosis of chronic lymphocytic leukemia with 17p deletion (17p- CLL). However, its applicability remains unclear. Since 2007, our leukemia service has referred 17p- CLL patients for alloSCT at presentation. In this study, the outcomes of these patients were reviewed retrospectively to determine whether they underwent alloSCT and why patients did not undergo alloSCT. Fifty-two patients with 17p- CLL, who were referred to the transplant service from 2007 to 2010, were identified. Of these patients, 32 (62%) patients did not undergo alloSCT, mainly because of treatment- or disease-related complications (n=15). The 2-year post-referral overall survival rates of the alloSCT and non-SCT groups were 64% and 25%, respectively (p = 0.001). These findings suggest that while alloSCT is an effective therapy in 17p- CLL patients, pre-SCT complications may preclude a significant proportion of patients from undergoing the procedure. PMID:24913509

  16. Plasma metabolomics profiling for the prediction of cytomegalovirus DNAemia and analysis of virus–host interaction in allogeneic stem cell transplant recipients.

    PubMed

    Monleón, Daniel; Giménez, Estela; Muñoz-Cobo, Beatriz; Morales, José Manuel; Solano, Carlos; Amat, Paula; Navarro, David

    2015-11-01

    Metabolomics analysis of biofluids is increasingly being recognized as a useful tool for the diagnosis and management of a number of infectious diseases. Here we showed that plasma metabolomics profiling by untargeted 1H nuclear magnetic resonance may allow the anticipation of the occurrence of cytomegalovirus (CMV) DNAemia in allogeneic stem cell transplant. For this purpose, key discriminatory metabolites were total glutathione, taurine, methylamine, trimethylamine N-oxide and lactate, all of which were upregulated in patients eventually developing CMV DNAemia. The overall classification accuracy (predictability) of the projection to latent structure discriminant analysis (PLS-DA) model in cross-validation technical replicates was 73 %. Increased levels of alanine, lactate and total fatty acids, and a shift in the fatty acid profile towards unsaturated species, were observed in patients with detectable CMV DNA in plasma. The classification accuracy of this PLS-DA model in cross-validation technical replicates was 81 %. Plasma metabolomics profiling may prove useful for identifying patients at highest risk for CMV DNAemia thus allowing early inception of antiviral therapy.

  17. Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study.

    PubMed

    Itonaga, Hidehiro; Iwanaga, Masako; Aoki, Kazunari; Aoki, Jun; Ishiyama, Ken; Ishikawa, Takayuki; Sakura, Toru; Fukuda, Takahiro; Najima, Yuho; Yujiri, Toshiaki; Mori, Takehiko; Kurokawa, Mineo; Nawa, Yuichiro; Uchida, Naoyuki; Morishita, Yoshihisa; Hashimoto, Hisako; Eto, Tetsuya; Hirokawa, Makoto; Morishima, Yasuo; Nagamura-Inoue, Tokiko; Atsuta, Yoshiko; Miyazaki, Yasushi

    2016-02-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option that may lead to improved outcomes in patients with chronic myelomonocytic leukemia (CMML). However, few studies have examined the impact of the grade of graft-versus-host disease (GVHD) on post-transplant outcomes for CMML. We retrospectively analyzed the outcomes of 141 patients with CMML who underwent allo-HSCT between 1987 and 2010, and achieved neutrophil engraftment. The effects of acute GVHD (aGVHD) or chronic GVHD (cGVHD) on overall survival (OS), leukemia-associated mortality (LAM), and transplant-related mortality were evaluated by hazards regression models, in which the onset date of aGVHD or cGVHD was treated as a time-dependent covariate. Grade I aGVHD was associated with better OS and lower LAM (P=0.042, P=0.033, respectively) than no GVHD in univariate analyses, but not in the multivariate analyses. The multivariate analyses demonstrated that extensive cGVHD significantly associated with better OS (Hazard Ratio [HR] 0.35 [95% confidence intervals (CI), 0.16-0.74]; P=0.007) and lower LAM (HR 0.36 [95% CI, 0.14-0.92]; P=0.033) in patients who were not in complete remission at transplantation. In conclusion, the occurrence of cGVHD may be an important factor affecting the outcomes of CMML patients who received transplantation. PMID:26754557

  18. Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia.

    PubMed

    Terwey, Theis Helge; Hemmati, Philipp Georg; Nagy, Marion; Pfeifer, Heike; Gökbuget, Nicola; Brüggemann, Monika; Le Duc, Tanja Melinh; le Coutre, Philipp; Dörken, Bernd; Arnold, Renate

    2014-10-01

    Little data are available on the relative merits of chimerism and minimal residual disease (MRD) monitoring for relapse prediction after allogeneic hematopoietic stem cell transplantation (HCT). We performed a retrospective analysis of serial chimerism assessments in 101 adult HCT recipients with acute lymphoblastic leukemia (ALL) and of serial MRD assessments in a subgroup of 22 patients. All patients had received myeloablative conditioning. The cumulative incidence of relapse was significantly higher in the patients with increasing mixed chimerism (in-MC) compared with those with complete chimerism, low-level MC, and decreasing MC, but the sensitivity of in-MC detection with regard to relapse prediction was only modest. In contrast, MRD assessment was highly sensitive and specific. Patients with MRD positivity after HCT had the highest incidence of relapse among all prognostic groups analyzed. The median time from MRD positivity to relapse was longer than the median time from detection of in-MC, but in some cases in-MC preceded MRD positivity. We conclude that MRD assessment is a powerful prognostic tool that should be included in the routine post-transplantation monitoring of patients with ALL, but chimerism analysis may provide additional information in some cases. Integration of these tools and clinical judgment should allow optimal decision making with regard to post-transplantation therapeutic interventions.

  19. Bilateral transplantation of allogenic adult human bone marrow-derived mesenchymal stem cells into the subventricular zone of Parkinson's disease: a pilot clinical study.

    PubMed

    Venkataramana, N K; Pal, Rakhi; Rao, Shailesh A V; Naik, Arun L; Jan, Majahar; Nair, Rahul; Sanjeev, C C; Kamble, Ravindra B; Murthy, D P; Chaitanya, Krishna

    2012-01-01

    The progress of PD and its related disorders cannot be prevented with the medications available. In this study, we recruited 8 PD and 4 PD plus patients between 5 to 15 years after diagnosis. All patients received BM-MSCs bilaterally into the SVZ and were followed up for 12 months. PD patients after therapy reported a mean improvement of 17.92% during "on" and 31.21% during "off" period on the UPDRS scoring system. None of the patients increased their medication during the follow-up period. Subjectively, the patients reported clarity in speech, reduction in tremors, rigidity, and freezing attacks. The results correlated with the duration of the disease. Those patients transplanted in the early stages of the disease (less than 5 years) showed more improvement and no further disease progression than the later stages (11-15 years). However, the PD plus patients did not show any change in their clinical status after stem cell transplantation. This study demonstrates the safety of adult allogenic human BM-MSCs transplanted into the SVZ of the brain and its efficacy in early-stage PD patients. PMID:22550521

  20. Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma.

    PubMed

    El-Cheikh, Jean; Crocchiolo, Roberto; Boher, Jean-Marie; Furst, Sabine; Stoppa, Anne-Marie; Ladaique, Patrick; Faucher, Catherine; Calmels, Boris; Castagna, Luca; Lemarie, Claude; De Colella, Jean-Marc Schiano; Coso, Diane; Bouabdallah, Reda; Chabannon, Christian; Blaise, Didier

    2012-06-01

    The purpose of this study was to assess the results of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning (RIC) from matched related donors (MRD) and unrelated donors (URD) in 40 patients with high-risk multiple myeloma (MM) in a single centre. Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had URD and MRD, respectively. Thirty-nine patients (98%) received one or more autologous transplantation. The median follow-up was 22 months (1-49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-IV acute GVHD was higher (47%) for the URD vs. (17%) for the MRD (P = 0.092). The cumulative incidence of chronic GVHD was no different between the two groups (24% vs. 30%, respectively). At 2 yr, the TRM probabilities were lower in the unrelated group 12% vs. 22% in the related group (P = 0.4). Also at 2 yrs, for patients receiving unrelated transplantation overall and progression-free survivals, 59% and 42%, respectively compared to patients with related donor transplantation, 66% and 44% (P = 0.241). In conclusion, these results suggest that URD in MM is feasible. The small number of patients with URD emphasizes the need to delineate indications and perform prospective protocols.

  1. Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies.

    PubMed

    Kennedy, Vanessa E; Savani, Bipin N; Greer, John P; Kassim, Adetola A; Engelhardt, Brian G; Goodman, Stacey A; Sengsayadeth, Salyka; Chinratanalab, Wichai; Jagasia, Madan

    2016-10-01

    Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

  2. Linezolid Induced Twice Pure Red Cell Aplasia in a Patient with Central Nervous System Infection after Allogeneic Stem Cell Transplantation.

    PubMed

    Hu, Wenqing; Shi, Bing; Liu, Lihui; He, Shengke; Ye, Liping; Tian, DengMei; Zhang, Yongqing

    2016-01-01

    Linezolid (LZD), severed as the first oxazolidinone antibiotic, was active against multidrug-resistant gram-positive strains. LZD can induce thrombocytopenia, anemia and leukocytopenia. Currently, reports on pure red cell aplasia (PRCA) cases induced by LZD are relatively rare (4-7). In this paper, we reported a patient with PRCA twice induced by LZD. A 37-year-old man was diagnosed with myelodysplatic syndrome (MDS) and underwent allo-HSCT from an unrelated donor with ABO blood type and leukocyte antigen (HLA)-matching. After HSCT for 2 years, the patient suffered from refractory fever and headache. He was first treated with empirical antifungal agent and antibiotics for central nervous system (CNS) infection, but then changed to LZD therapy for little effect. Twenty-eight days after LZD treatment, the symptom improved significantly but the hemoglobin declined to 70 g/L and the reticulocyte level was only 0.23%. The LZD therapy was stopped and the fever and headache symptoms reoccurred 1 week latter. Then, erythropoietin (EPO) and halved dosage of LZD were used for treatment. The CNS infection and the anemia symptom relieved gradually and the level of hemoglobin and reticulocyte declined again. After blood transfusion, the half dose of LZD was sustained without anaemia recovery. In summary, patients with anemia, myelosuppressants history or potential abnormal proliferation of T cells may suffer PRCA with long term LZD treatment. The monitoring of complete blood count and reticulocyte count were necessary during LZD therapy. If the clinical condition permits, LZD dosage reduction and blood transfusion should be considered. PMID:27642338

  3. Linezolid Induced Twice Pure Red Cell Aplasia in a Patient with Central Nervous System Infection after Allogeneic Stem Cell Transplantation

    PubMed Central

    Hu, Wenqing; Shi, Bing; Liu, Lihui; He, Shengke; Ye, Liping; Tian, DengMei; Zhang, Yongqing

    2016-01-01

    Linezolid (LZD), severed as the first oxazolidinone antibiotic, was active against multidrug-resistant gram-positive strains. LZD can induce thrombocytopenia, anemia and leukocytopenia. Currently, reports on pure red cell aplasia (PRCA) cases induced by LZD are relatively rare (4-7). In this paper, we reported a patient with PRCA twice induced by LZD. A 37-year-old man was diagnosed with myelodysplatic syndrome (MDS) and underwent allo-HSCT from an unrelated donor with ABO blood type and leukocyte antigen (HLA)-matching. After HSCT for 2 years, the patient suffered from refractory fever and headache. He was first treated with empirical antifungal agent and antibiotics for central nervous system (CNS) infection, but then changed to LZD therapy for little effect. Twenty-eight days after LZD treatment, the symptom improved significantly but the hemoglobin declined to 70 g/L and the reticulocyte level was only 0.23%. The LZD therapy was stopped and the fever and headache symptoms reoccurred 1 week latter. Then, erythropoietin (EPO) and halved dosage of LZD were used for treatment. The CNS infection and the anemia symptom relieved gradually and the level of hemoglobin and reticulocyte declined again. After blood transfusion, the half dose of LZD was sustained without anaemia recovery. In summary, patients with anemia, myelosuppressants history or potential abnormal proliferation of T cells may suffer PRCA with long term LZD treatment. The monitoring of complete blood count and reticulocyte count were necessary during LZD therapy. If the clinical condition permits, LZD dosage reduction and blood transfusion should be considered. PMID:27642338

  4. Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

    PubMed

    Liu, Na; Ning, Hong-Mei; Hu, Liang-Ding; Jiang, Min; Xu, Chen; Hu, Jiang-Wei; Wang, Jun; Li, Yu-Hang; Li, Bo-Tao; Lou, Xiao; Yang, Fan; Chen, Jian-Lin; Su, Yong-Feng; Li, Meng; Wang, Hong-Ye; Ren, Jing; Feng, Yue-Qian; Zhang, Bin; Wang, Dan-Hong; Chen, Hu

    2015-12-01

    To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group. PMID:26530539

  5. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up.

    PubMed

    Oyekunle, A A; Kröger, N; Zabelina, T; Ayuk, F; Schieder, H; Renges, H; Fehse, N; Waschke, O; Fehse, B; Kabisch, H; Zander, A R

    2006-01-01

    We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia=25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n=22; TBI/Cy/VP, n=17; others, n=5) followed by marrow or peripheral blood transplant (n=23/21) from unrelated or related donors (n=28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n=15) and infections (n=12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts < or =20% and time to transplant < or =1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with < or =20% marrow blast.

  6. Efficacy and Safety of a Preemptive Antiviral Therapy Strategy Based on Combined Virological and Immunological Monitoring for Active Cytomegalovirus Infection in Allogeneic Stem Cell Transplant Recipients

    PubMed Central

    Navarro, David; Amat, Paula; de la Cámara, Rafael; López, Javier; Vázquez, Lourdes; Serrano, David; Nieto, José; Rovira, Monserrat; Piñana, José Luis; Giménez, Estela; Solano, Carlos

    2016-01-01

    Background. Preemptive antiviral therapy for active cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients (Allo-SCT) results in overtreatment and a high rate of recurrences. Monitoring of CMV-specific T-cell immunity may help to individualize treatments and minimize these problems. Methods. We conducted a prospective, multicenter, matched comparison-group study to evaluate the efficacy and safety of a novel strategy that consisted of interrupting anti-CMV therapy upon CMV DNAemia clearance and concurrent detection of phosphoprotein 65/immediate-early-1-specific interferon-γ-producing CD8+ T cells at levels of >1 cell/µL (within 30 days after the initiation of therapy). Immunological monitoring was performed on days +7, +14, +21, and +28 after treatment initiation. The primary endpoint was the cumulative incidence of recurrent DNAemia within 2 months after treatment cessation. Secondary endpoints were the length of antiviral treatment courses and the incidence of hematological toxicity. Results. Sixty-one patients were enrolled in the study group. Fifty-six patients were included in the matched-control group. Eleven patients (18%) fulfilled the criteria for antiviral treatment interruption. The cumulative incidence of recurrent CMV DNAemia was significantly lower (P = .02) in these patients than in patients in the comparative groups. Likewise, the length of antiviral treatment courses was significantly shorter in these patients than that in patients in the matched-control group (P = .003). No significant differences in the incidence of hematological toxicity was observed between the comparative groups. Conclusions. Our data support the clinical utility of combining immunological and virological monitoring for the management of CMV infection in a subset of Allo-SCT recipients. PMID:27419179

  7. Allogeneic Stem Cell Transplantation in Congenital Hemoglobinopathies Using a Tailored Busulfan-Based Conditioning Regimen: Single-Center Experience.

    PubMed

    Zaidman, Irina; Rowe, Jacob M; Khalil, Abdalla; Ben-Arush, Myriam; Elhasid, Ronit

    2016-06-01

    Hematopoietic stem cell transplantation (HSCT) is the only proven curative option for patients with hemoglobinopathies, both thalassemia and sickle cell anemia (SCA). A busulfan-based myeloablative conditioning regimen is the standard of care for HSCT in these patients, although increased treatment-related morbidity, including veno-occlusive disease (VOD), has been demonstrated. Thirty-eight pediatric patients, median age 8 years (range, 6 months to 22 years), suffering from hemoglobinopathy were treated at Rambam Medical Center in Haifa, Israel, between 1998 and 2011. Thirty-four patients had thalassemia major and 4 had SCA. The 38 patients underwent 40 HSCTs, 34 of which were first transplants and 6 second transplants. Most transplants (32/40) were from matched sibling donors. Sources of stem cells were peripheral blood in 30 transplants, bone marrow in 7 transplants, and cord blood in 3 transplants. All received different customized busulfan-based conditioning regimens tailored by pharmacokinetic analysis of busulfan levels. Primary engraftment occurred in 37 of 40 transplants. Neutrophil engraftment (>.5 × 10(9)/L) occurred at a median of 15.3 days post-transplantation (range, 10 to 45). Platelet transfusion independence (>20 × 10(9)/L) occurred at a median of 22.3 days (range, 11 to 60). The rate of 5-year overall survival for thalassemia patients after first transplantation was 90.5% ± 5.3%. The rate of 5-year thalassemia-free survival was 81.7% ± 6.8%. Cumulative incidence of acute graft-versus-host disease (GVHD) was 17.6%. Rate of grades III to IV GVHD was 8.8%. Cumulative incidence of chronic GVHD was 23.5%, with 11.8% incidence of extensive chronic GVHD. One patient developed VOD. Full donor chimerism occurred in 36.4% of patients with class 1 + 2 thalassemia, compared with 78.6% in class 3 thalassemia (P = .049). Overall survival above 90% in patients undergoing their first transplant was demonstrated using busulfan

  8. Production of good manufacturing practice-grade cytotoxic T lymphocytes specific for Epstein-Barr virus, cytomegalovirus and adenovirus to prevent or treat viral infections post-allogeneic hematopoietic stem cell transplant.

    PubMed

    Sili, Uluhan; Leen, Ann M; Vera, Juan F; Gee, Adrian P; Huls, Helen; Heslop, Helen E; Bollard, Catherine M; Rooney, Cliona M

    2012-01-01

    Infections with a range of common community viruses remain a major cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation. T cells specific for cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenoviruses can safely prevent and infections with these three most common culprits, but the manufacture of individual T cell lines for each virus would be prohibitive in terms of time and cost. We have demonstrated that T cells specific for all three viruses can be manufactured in a single culture using monocytes and EBV-transformed B lymphoblastoid cell lines (LCLs), both transduced with an adenovirus vector expressing pp65 of CMV, as antigen-presenting cells. Trivirus-specific T cell lines produced from healthy stem cell donors could prevent and treat infections with all three viruses, not only in the designated recipient, but in unrelated, partially-HLA-matched third party recipients. We now provide the details and logistics of T cell manufacture.

  9. Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes

    PubMed Central

    Toor, Amir A.; Sabo, Roy T.; Roberts, Catherine H.; Moore, Bonny L.; Salman, Salman R.; Scalora, Allison F.; Aziz, May T.; Shubar Ali, Ali S.; Hall, Charles E.; Meier, Jeremy; Thorn, Radhika M.; Wang, Elaine; Song, Shiyu; Miller, Kristin; Rizzo, Kathryn; Clark, William B.; McCarty, John M.; Chung, Harold M.; Manjili, Masoud H.; Neale, Michael C.

    2016-01-01

    Systems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3+ cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3+ at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk. PMID:25849208

  10. Cure of a patient with profoundly chemotherapy-refractory primary mediastinal large B-cell lymphoma: role of rituximab, high-dose therapy, and allogeneic stem cell transplantation.

    PubMed

    Nath, Shriram V; Seymour, John F

    2005-07-01

    Patients with primary large B-cell lymphomas of the mediastinum (PMBL) who suffer early relapse have a low likelihood of achieving a prolonged second remission with conventional salvage therapy. Here we describe the case of a 33-year-old woman with PMBL refractory to 6 lines of therapy before undergoing salvage therapy with rituximab, ifosfamide and etoposide followed by high-dose therapy, autologous transplantation, and sequential non-myeloablative allogeneic transplantation, who remains in ongoing complete remission for more than 39 months and is apparently cured. The specific roles of the components of the successful salvage therapy are discussed. PMID:16019561

  11. Nonmyeloablative allogeneic hematopoietic cell transplantation

    PubMed Central

    Storb, Rainer; Sandmaier, Brenda M.

    2016-01-01

    Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease. PMID:27132278

  12. Is mobilized peripheral blood comparable with bone marrow as a source of hematopoietic stem cells for allogeneic transplantation from HLA-identical sibling donors? A case-control study

    PubMed Central

    Gallardo, David; de la Cámara, Rafael; Nieto, Jose B.; Espigado, Ildefonso; Iriondo, Arturo; Jiménez-Velasco, Antonio; Vallejo, Carlos; Martín, Carmen; Caballero, Dolores; Brunet, Salut; Serrano, David; Solano, Carlos; Ribera, Josep M.; de la Rubia, Javier; Carreras, Enric

    2009-01-01

    Background Granulocyte colony-stimulating factor mobilized peripheral blood stem cells are increasingly used instead of bone marrow as a stem cell source for transplantation. Whereas this change is almost complete for autologous transplantation, there are some concerns when considering allogeneic transplants. Design and Methods We performed a retrospective case-control study including 820 adult patients who had received an allogeneic stem cell transplant from an HLA-identical sibling donor. Quality of life (QoL) was assessed in 150 patients using the EORTC Quality of Life Questionnaire C30 (QLQ-C30). Results There were no statistically significant differences in overall survival at ten years (bone marrow: 48.9% vs. peripheral blood stem cells: 39.8%; p=0.621), transplant-related mortality (bone marrow: 28.9% vs. peripheral blood stem cells: 34.4%; p=0.682) or relapse incidence at 9 years (29.4% vs. 35.2%, respectively; p=0.688). Similar outcomes were maintained independently of the phase of the disease. However, multivariate analysis identified a higher incidence of acute graft-versus-host disease grades II-IV (p: 0.023; Hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.05–1.89) and grades III-IV (p: 0.006; HR: 1.89; 95% CI: 1.20–2.98), in the peripheral blood stem cells-stem cell transplant group. As previously described, extensive chronic graft-versus-host disease was also more frequent in the peripheral blood stem cells group (28% vs. 15.6%; p<0.001). Patients transplanted with peripheral blood stem cells had significant impairment of role and social functioning. Conclusions Although overall survival was not affected by the stem cell source, peripheral blood stem cell transplants were associated with a higher risk of both acute and chronic GvHD. Global quality of life was similar in both groups, but patients transplanted with peripheral blood stem cells showed worse role and social functioning scores, probably related to the increased incidence of

  13. Early donor chimerism levels predict relapse and survival after allogeneic stem-cell transplantation with reduced intensity conditioning

    PubMed Central

    Reshef, Ran; Hexner, Elizabeth O.; Loren, Alison W.; Frey, Noelle V.; Stadtmauer, Edward A.; Luger, Selina M.; Mangan, James K.; Gill, Saar I.; Vassilev, Pavel; Lafferty, Kathryn A.; Smith, Jacqueline; Van Deerlin, Vivianna M.; Mick, Rosemarie; Porter, David L.

    2014-01-01

    The success of hematopoietic stem-cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for pre-emptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease and survival in a cohort of 121 patients who were allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (HR=0.90, p<0.001), relapse-free survival (HR=0.89, p<0.001) and overall survival (HR=0.94, p=0.01). Day-30 T-cell chimerism levels were also significantly associated with relapse (HR=0.97, p=0.002), relapse-free survival (HR=0.97, p<0.001) and overall survival (HR=0.99, p=0.05). Multivariate models that included T-cell chimerism provided a better prediction for these outcomes compared to whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient prior to transplant, highlighting the impact of pre-transplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT. PMID:25016197

  14. Spiritual Well-Being in Hispanic and Non-Hispanic Survivors of Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Prince, Patricia; Mitchell, Sandra A; Wehrlen, Leslie; Childs, Richard; Savani, Bipin; Yang, Li; Bevans, Margaret

    2015-01-01

    Research suggests that spiritual well-being positively contributes to quality of life during and following cancer treatment. This relationship has not been well-described in ethnically diverse survivors of allogeneic transplantation.  This study compares spiritual well-being and quality of life of Hispanic (n = 69) and non-Hispanic (n = 102) survivors. Hispanic participants were significantly younger and reported significantly greater spiritual well-being than non-Hispanic survivors. Survivors with higher spiritual well-being had significantly better quality of life. Meaning and Peace significantly predicted quality of life. Although Hispanic survivors report greater spiritual well-being, Meaning and Peace, irrespective of ethnicity, have a salutary effect on quality of life. PMID:26315721

  15. Spiritual Well-Being in Hispanic and Non-Hispanic Survivors of Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Prince, Patricia; Mitchell, Sandra A; Wehrlen, Leslie; Childs, Richard; Savani, Bipin; Yang, Li; Bevans, Margaret

    2015-01-01

    Research suggests that spiritual well-being positively contributes to quality of life during and following cancer treatment. This relationship has not been well-described in ethnically diverse survivors of allogeneic transplantation.  This study compares spiritual well-being and quality of life of Hispanic (n = 69) and non-Hispanic (n = 102) survivors. Hispanic participants were significantly younger and reported significantly greater spiritual well-being than non-Hispanic survivors. Survivors with higher spiritual well-being had significantly better quality of life. Meaning and Peace significantly predicted quality of life. Although Hispanic survivors report greater spiritual well-being, Meaning and Peace, irrespective of ethnicity, have a salutary effect on quality of life.

  16. Spiritual Well-Being in Hispanic and Non-Hispanic Survivors of Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Prince, Patricia; Mitchell, Sandra A.; Wehlen, Leslie; Childs, Richard; Savani, Bipin; Yang, Li; Bevans, Margaret

    2016-01-01

    Research suggests that spiritual well-being positively contributes to quality of life during and following cancer treatment. This relationship has not been well-described in ethnically diverse survivors of allogeneic transplantation. This study compares spiritual well-being and quality of life of Hispanic (n=69) and non-Hispanic (n=102) survivors. Hispanic participants were significantly younger, and reported significantly greater spiritual well-being than non-Hispanic survivors. Survivors with higher spiritual well-being had significantly better quality of life. Meaning and Peace significantly predicted quality of life. Although Hispanic survivors report greater spiritual well-being, Meaning and Peace, irrespective of ethnicity, have a salutary effect on quality of life. PMID:26315721

  17. Reduced IL-35 levels are associated with increased platelet aggregation and activation in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Zhang, Xiaohui; Zhou, Yi; Xu, Lanping; Han, Wei; Chen, Huan; Chen, Yuhong; Fu, Haixia; Zhou, Shiyuan; Zhao, Jingzhong; Wang, Qianming; Feng, Feier; Zhu, Xiaolu; Liu, Kaiyan; Huang, Xiaojun

    2015-05-01

    Acute graft-versus-host disease (aGVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that suppresses the immune response. This prospective study explored IL-35 plasma levels in 65 patients after HSCT. The results revealed that the peripheral blood of patients with grades III-IV aGVHD (23.46 ng/ml) had reduced IL-35 compared to transplanted patients with grades I-II aGVHD (40.26 ng/ml, p < 0.01) or patients without aGVHD (41.40 ng/ml, p < 0.05). Allografts, including granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cell (PBPC) and G-CSF-primed bone marrow (GBM), from 38 patients were analyzed for IL-35 levels with respect to aGVHD. The patients who received lower levels of IL-35 cells in the GBM (28.0 ng/ml, p = 0.551) or lower levels of IL-35 in PBPC (53.46 ng/ml, p = 0.03) exhibited a higher incidence of aGVHD. Patients with aGVHD have increased platelet aggregation. IL-35 was added to patient blood in vitro, and platelet aggregation was inhibited by IL-35 in a dose-dependent manner. The markers of platelet activation (CD62P/PAC-1) can also be inhibited by IL-35. The results indicate that IL-35 may affect the development of aGVHD by inhibiting platelet activation and aggregation. Our data suggests that IL-35 represents a potentially effective therapeutic agent against aGVHD after allo-HSCT.

  18. Role of acute graft-versus-host disease in the risk of bacteremia and invasive fungal disease after allogeneic hemopoietic stem cell transplantation in children. Results from a single-center observational study.

    PubMed

    Castagnola, Elio; Bagnasco, Francesca; Bandettini, Roberto; Caviglia, Ilaria; Morreale, Giuseppe; Lanino, Edoardo; Giardino, Stefano; Moroni, Cristina; Haupt, Riccardo; Faraci, Maura

    2014-07-01

    Data on epidemiology of severe infectious complications, ie, bacteremia or invasive fungal disease (IFD), in children with acute graft-versus-host disease (aGVHD) after allogeneic hemopoietic stem cell transplantation (HSCT) are scarce. In a retrospective, single-center study, we analyzed the risk (hazard ratio [HR]) and the rate (episodes/1000 patients days at risk) of bacteremias and IFD in children receiving allogeneic HSCT, according to the type of donor (matched related [MRD] or alternative [AD]) and presence and grade of aGVHD. From 2000 to 2009, 198 children receiving 217 allogeneic HSCT developed 134 severe infectious episodes (103 bacteremias and 31 IFD). The type of donor (AD versus MRD) was the most important risk factor for the severe infections (P = .0052). In separate multivariable analysis for bacteremia and IFD, children receiving an AD HSCT had increased HR and rate of bacteremia compared with those receiving a MRD transplantation (P = .0171 and P = .0001, respectively), whereas the HR and the rate of IFD were significantly influenced by the grade of aGVHD (P = .0002 and P < .0001, respectively). Finally, infectious episodes occurred late after HSCT, especially in presence of severe aGVHD, and bacteremias were 3 to 6 times more frequent than IFD. These data may be important to design management strategies of infections in pediatric allogeneic HSCT.

  19. Pretransplant pulmonary function tests predict risk of mortality following fractionated total body irradiation and allogeneic peripheral blood stem cell transplant

    SciTech Connect

    Singh, Anurag K. . E-mail: singan@mail.nih.gov; Karimpour, Shervin E.; Savani, Bipin N.; Guion, Peter M.S.; Hope, Andrew J.; Mansueti, John R.; Ning, Holly; Altemus, Rosemary M. Ph.D.; Wu, Colin O.; Barrett, A. John

    2006-10-01

    Purpose: To determine the value of pulmonary function tests (PFTs) done before peripheral blood stem cell transplant (PBSCT) in predicting mortality after total body irradiation (TBI) performed with or without dose reduction to the lung. Methods and Materials: From 1997 to 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI before PBSCT. With regimen A (n = 85), patients were treated without lung dose reduction to 13.6 gray (Gy). In regimen B (n = 35), total body dose was decreased to 12 Gy (1.5 Gy twice per day for 4 days) and lung dose was limited to 9 Gy by use of lung shielding. In regimen C (n = 26), lung dose was reduced to 6 Gy. All patients received PFTs before treatment, 90 days after treatment, and annually. Results: Median follow-up was 44 months (range, 12-90 months). Sixty-one patients had combined ventilation/diffusion capacity deficits defined as both a forced expiratory volume in the first second (FEV{sub 1}) and a diffusion capacity of carbon dioxide (DLCO) <100% predicted. In this group, there was a 20% improvement in one-year overall survival with lung dose reduction (70 vs. 50%, log-rank test p = 0.042). Conclusion: Among those with combined ventilation/diffusion capacity deficits, lung dose reduction during TBI significantly improved survival.

  20. Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease?

    PubMed

    Radujkovic, Aleksandar; Guglielmi, Cesare; Bergantini, Stefania; Iacobelli, Simona; van Biezen, Anja; Milojkovic, Dragana; Gratwohl, Alois; Schattenberg, Antonius V M B; Verdonck, Leo F; Niederwieser, Dietger W; de Witte, Theo; Kröger, Nicolaus; Olavarria, Eduardo

    2015-07-01

    Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD-free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3(+) cells ≥ 50 × 10(6)/kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD.

  1. Brentuximab Vedotin in Patients With Hodgkin Lymphoma and a Failed Allogeneic Stem Cell Transplantation: Results From a Named Patient Program at Four Italian Centers

    PubMed Central

    Ricci, Francesca; Dalto, Serena; Mazza, Rita; Malagola, Michele; Patriarca, Francesca; Viviani, Simonetta; Russo, Domenico; Giordano, Laura; Castagna, Luca; Corradini, Paolo; Santoro, Armando

    2015-01-01

    Background. Brentuximab vedotin (BV) has demonstrated an extraordinary efficacy in heavily pretreated classical Hodgkin lymphoma (cHL) patients, targeting CD30-positive cells; however, limited data have been reported on the efficacy of BV in cHL patients failing allogeneic stem cell transplantation (allo-SCT). The aim of this study was to retrospectively evaluate the efficacy and safety of BV in a multicenter setting of cHL relapsing or progressing after allo-SCT. Methods. Sixteen BV-naïve patients with recurrent cHL after allo-SCT were included in a compassionate use program and treated with intravenous BV at the dose of 1.8 mg/kg of body weight every 3 weeks for a maximum of 16 cycles. Results. The objective response rate was 69%. Five patients (31%) had complete remission, and 6 (37%) had partial remission. Stable disease was observed in 4 patients (25%), and progressive disease was observed in 1 (6%). After median follow-up of 26 months (range: 5–30 months), median progression-free survival (PFS), overall survival (OS), and duration of response were 7, 25, and 5 months, respectively. The 2-year PFS and OS were 20% and 61%, respectively. Grade 3–4 hematological adverse events included anemia (15%), thrombocytopenia (12%), and neutropenia (18%). Grade 3 peripheral sensory neuropathy occurred in 2 patients (12%). Conclusion. BV therapy is an effective and safe approach for achieving transient disease control in cHL patients with failed allo-SCT. To improve disease control, future studies should explore the combination of BV with targeted agents. PMID:25669663

  2. Atorvastatin for the Prophylaxis of Acute Graft-versus-Host Disease in Patients Undergoing HLA-Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT).

    PubMed

    Efebera, Yvonne A; Geyer, Susan; Andritsos, Leslie; Vasu, Sumithira; Jaglowski, Samantha; Bingman, Anissa; Blum, William; Klisovic, Rebecca; Hofmeister, Craig C; Benson, Don M; Penza, Sam; Elder, Patrick; Cortright, Katie; Kitzler, Rhonda; Coombes, Kevin; O'Donnell, Lynn; Daneault, Beth; Bradbury, Hillary; Zhang, Jianying; Chen, Xilin; Garman, Sabrina; Ranganathan, Parvathi; Yu, Xueyan; Hofstetter, Jessica; Yu, Jianhua; Garzon, Ramiro; Scrape, Scott R; Lozanski, Gerard; Devine, Steven M

    2016-01-01

    Statins possess potent immunomodulatory effects that may play a role in preventing acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). We performed a phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40 mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n = 40) received atorvastatin (40 mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades II to IV aGVHD at day 100. Atorvastatin was well tolerated, with no attributable grades III to IV toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grades II to IV aGVHD were 30% (95% confidence interval [CI], 17% to 45%) and 40% (95% CI, 25% to 55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI, 32% to 69%). One-year nonrelapse mortality and relapse incidences were 5.5% (95% CI, .9% to 16.5%) and 38% (95% CI, 18% to 47%), respectively. One-year progression-free and overall survival rates were 54% (95% CI, 38% to 71%) and 82% (95% CI, 69% to 94%). One-year GVHD-free, relapse-free survival was 27% (95% CI, 16% to 47%). These results did not differ from our historical control subjects (n = 96). Although safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone.

  3. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission

    PubMed Central

    Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

    2016-01-01

    Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia. PMID:26883100

  4. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

    PubMed Central

    Shono, Yusuke; Docampo, Melissa D.; Peled, Jonathan U.; Perobelli, Suelen M.; Velardi, Enrico; Tsai, Jennifer J.; Slingerland, Ann E.; Smith, Odette M.; Young, Lauren F.; Gupta, Jyotsna; Lieberman, Sophia R.; Jay, Hillary V.; Ahr, Katya F.; Rodriguez, Kori A. Porosnicu; Xu, Ke; Calarfiore, Marco; Poeck, Hendrik; Caballero, Silvia; Devlin, Sean M.; Rapaport, Franck; Dudakov, Jarrod A.; Hanash, Alan M.; Gyurkocza, Boglarka; Murphy, George F.; Gomes, Camilla; Liu, Chen; Moss, Eli L.; Falconer, Shannon B.; Bhatt, Ami S.; Taur, Ying; Pamer, Eric G.

    2016-01-01

    After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after

  5. Role of Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem-Cell Transplantation in Older Patients With De Novo Myelodysplastic Syndromes: An International Collaborative Decision Analysis

    PubMed Central

    Koreth, John; Pidala, Joseph; Perez, Waleska S.; Deeg, H. Joachim; Garcia-Manero, Guillermo; Malcovati, Luca; Cazzola, Mario; Park, Sophie; Itzykson, Raphael; Ades, Lionel; Fenaux, Pierre; Jadersten, Martin; Hellstrom-Lindberg, Eva; Gale, Robert Peter; Beach, C.L.; Lee, Stephanie J.; Horowitz, Mary M.; Greenberg, Peter L.; Tallman, Martin S.; DiPersio, John F.; Bunjes, Donald; Weisdorf, Daniel J.; Cutler, Corey

    2013-01-01

    Purpose Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. Patients and Methods A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q– syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). Results For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. Conclusion For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC

  6. Persistence of Cytogenetic Abnormalities at Complete Remission After Induction in Patients With Acute Myeloid Leukemia: Prognostic Significance and the Potential Role of Allogeneic Stem-Cell Transplantation

    PubMed Central

    Chen, Yiming; Cortes, Jorge; Estrov, Zeev; Faderl, Stefan; Qiao, Wei; Abruzzo, Lynne; Garcia-Manero, Guillermo; Pierce, Sherry; Huang, Xuelin; Kebriaei, Partow; Kadia, Tapan; De Lima, Marcos; Kantarjian, Hagop; Ravandi, Farhad

    2011-01-01

    Purpose To determine the prognostic impact of persistent cytogenetic abnormalities at complete remission (CR) on relapse-free survival (RFS) and overall survival (OS) in patients with acute myeloid leukemia (AML) and to examine the potential role of allogeneic stem-cell transplantation (SCT) in this setting. Patients and Methods Data from 254 adult patients with AML (excluding acute promyelocytic leukemia) who achieved CR after induction chemotherapy on various first-line protocols were examined. Results Median follow-up for surviving patients was 43 months. Patients with cytogenetic abnormalities at CR (n = 71) had significantly shorter RFS (P = .001) and OS (P < .001) compared with patients with normal cytogenetics at CR (n = 183); 3-year RFS was 15% and 45%, and 3-year OS was 15% and 56%, respectively. Among the patients with persistent cytogenetic abnormalities at CR, those who underwent SCT in first CR (CR1; n = 15) had better RFS and OS compared to those without SCT (n = 56; P = .04 and .06, respectively). In multivariate analysis, persistent cytogenetic abnormalities at CR was an independent predictor for RFS (P < .001) and OS (P = .001), but among patients with persistent cytogenetic abnormalities at CR, no significant differences in OS (P = .25) was observed between those who did or did not receive SCT with a trend favoring SCT for RFS (P = .08). Conclusion Persistent cytogenetically abnormal cells at CR predict a significantly shorter RFS and OS. SCT in CR1 may improve the clinical outcome of patients lacking cytogenetic remission after induction although this depends on patient selection. PMID:21555694

  7. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia

    PubMed Central

    2013-01-01

    Background Peripheral vascular disease of the lower extremities comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI). Bone marrow derived Mesenchymal Stem Cells (BM- MSCs) may ameliorate the consequences of CLI due to their combinatorial potential for inducing angiogenesis and immunomodulatory environment in situ. The primary objective was to determine the safety of BM- MSCs in patients with CLI. Methods Prospective, double blind randomized placebo controlled multi-center study was conducted in patients with established CLI as per Rutherford classification in category II-4, III-5, or III-6 with infra-inguinal arterial occlusive disease and were not suitable for or had failed revascularization treatment. The primary end point was incidence of treatment – related adverse events (AE). Exploratory efficacy end points were improvement in rest pain, increase in Ankle Brachial Pressure Index (ABPI), ankle pressure, healing of ulcers, and amputation rates. Twenty patients (BM-MSC: Placebo = 1:1) were administered with allogeneic BM-MSCs at a dose of 2 million cells/kg or placebo (PlasmaLyte A) at the gastrocnemius muscle of the ischemic limb. Results Improvement was observed in the rest pain scores in both the arms. Significant increase in ABPI and ankle pressure was seen in BM-MSC arm compared to the placebo group. Incidence of AEs in the BM-MSC arm was 13 vs. 45 in the placebo arm where as serious adverse events (SAE) were similar in both the arms (5 in BM-MSC and 4 in the placebo group). SAEs resulted in death, infected gangrene, amputations in these patients. It was observed that the SAEs were related to disease progression and not related to stem cells. Conclusion BM-MSCs are safe when injected IM at a dose of 2 million cells/kg body weight. Few efficacy parameters such as ABPI and ankle pressure showed positive trend warranting further studies. Trial registration NIH website (http

  8. Improved clinical outcomes of high risk β thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with a treosulfan based conditioning regimen and peripheral blood stem cell grafts.

    PubMed

    Mathews, Vikram; George, Biju; Viswabandya, Auro; Abraham, Aby; Ahmed, Rayaz; Ganapule, Abhijeet; Sindhuvi, Eunice; Lakshmi, Kavitha M; Srivastava, Alok

    2013-01-01

    Improving clinical outcomes among high risk Class III β thalassemia major patients (Class IIIHR) receiving an allogeneic SCT remains a challenge. From October, 2009 a treosulfan based regimen (TreoFluT) was used for all consecutive Class III patients (n = 50). The clinical outcomes were compared with the historical conventional busulfan (BuCy) based regimen (n = 139). Use of TreoFluT was associated with a significantly reduced incidence of sinusoidal obstruction syndrome (SOS) among Class IIIHR cases (78% to 30%; P = 0.000) and early TRM (46% to 13%; p = 0.005). There was also a trend towards better engraftment in the Class IIIHR subset (P = 0.055). However, the use of bone marrow (BM) as source of stem cells along with the TreoFluT regimen was associated with 50% early mixed chimerism which reduced to 8.5% with the use of a peripheral blood stem cell graft (PBSC). Use of a PBSC graft was not associated with a significant increase in the incidence of acute or chronic graft versus host disease (GVHD). The overall and event free survival was significantly better among the Class IIIHR subset with the use of TreoFluT Vs. BuCy (86.6 ± 7.3 Vs. 39.4 ± 6.8%; P = 0.002 and 77.8 ± 8.8 Vs. 32.4 ± 6.5%; P = 0.003 respectively). A TreoFluT conditioning regimen with a PBSC graft can significantly improve clinical outcomes of Class IIIHR patients.

  9. A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.

    PubMed

    Osunkwo, Ifeyinwa; Bessmertny, Olga; Harrison, Lauren; Cheung, Ying-Kuen; Van de Ven, Carmella; del Toro, Gustavo; Garvin, James; George, Diane; Bradley, M Brigid; Wolownik, Karen; Wischhover, Cheryl; Levy, Joseph; Skerrett, Donna; Cairo, Mitchell S

    2004-04-01

    Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK

  10. Efficacy of mouth rinse in preventing oral mucositis in patients receiving high-dose cytarabine for allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mori, Takehiko; Hasegawa, Kaori; Okabe, Ai; Tsujimura, Natsuki; Kawata, Yusuke; Yashima, Tomoko; Kobayashi, Naoko; Kondo, Sakiko; Aisa, Yoshinobu; Kato, Jun; Tsunoda, Kazuyuki; Nagai, Tetsuo; Nakagawa, Taneaki; Shigematsu, Naoyuki; Kubo, Atsushi; Ikeda, Yasuo; Okamoto, Shinichiro

    2008-12-01

    High-dose cytarabine is one of the major components of the conditioning regimen for hematopoietic stem cell transplantation (HSCT), and frequently causes severe oral mucositis. We have recently demonstrated that cytarabine is excreted into the saliva in patients receiving high-dose cytarabine, and proposed that it might locally and directly contribute to the development of oral mucositis. Therefore, this study was performed to assess whether removing the excreted cytarabine in the saliva by intensive mouth rinse during high-dose cytarabine infusion could reduce the incidence of oral mucositis. Fifteen patients with hematologic malignancies undergoing allogeneic HSCT who received total body irradiation (12 Gy) and high-dose cytarabine at a dose of 3 g/m(2) every 12 h for 4 days as a conditioning were evaluated. Patients were instructed to rinse their mouths using ice-cold water every 10 min, starting simultaneously with the 2-h cytarabine infusion and continuing up to 1 h after completion of each infusion. Oral mucositis was graded on a daily basis according to the National Cancer Institute, Common Toxicity Criteria. Thirty-five patients who previously underwent the same conditioning without mouth rinse served as controls. The incidence of Grades 2-3 and Grade 3 oral mucositis was significantly reduced in patients who performed mouth rinse as compared with the controls (40 vs. 80%, P = 0.009; 0 vs. 25. 7%, P = 0.02). In conclusion, mouth rinse during and shortly after high-dose cytarabine infusion could be an effective and inexpensive measure in reducing the incidence of moderate to severe oral mucositis caused by high-dose cytarabine. This finding strongly suggests the role of cytarabine excretion in the saliva in the development of cytarabine-associated oral mucositis.

  11. [The role of pre-transplant debulking treatment in patients undergoing allogeneic stem cell transplantation for high-risk myelodysplastic syndrome].

    PubMed

    Gauthier, Jordan; Damaj, Gandhi; Yakoub-Agha, Ibrahim

    2015-04-01

    Treatment of myelodysplastic syndromes (MDS) remains unsatisfactory. Variable success in the correction of blood cytopenias, reduction of the proportion of marrow myeloblasts, and normalization of cytogenetics has been achieved with a variety of treatment strategies, including the use of immunosuppressive drugs, differentiating agents, conventional chemotherapy, and hypomethylating agents (HMAs) However, in general, responses have not been complete and have been of limited duration; prolongation of survival, if achieved, on average has been in the range of months. Currently, allogeneic hematopoietic stem-cell transplantation (allo-SCT) remains the only approach with curative potential for patients with higher risk/advanced MDS. Yet, despite the beneficial effects of allo-SCT, post-transplant relapse is a major cause of failure. Debulking prior to transplant treatment in patients with MDS is a matter of debate. The achievement of complete remission (CR) before allo-SCT improves post-transplantation outcome, although it is not clear whether this reflects the selection of patients with more responsive disease or is related to a reduction in disease burden. Higher CR rates in patients with MDS are obtained with induction chemotherapy (ICT) than with hypomethylating agents (HMAs), although HMAs may be active in patients with complex karyotypes in whom ICT almost invariably fails. Furthermore, HMAs have a good toxicity profile compared with ICT and may therefore be considered especially in older patients and in patients with comorbidities. However, all interventions aimed at reducing disease burden before allo-SCT expose patients to the risk of complications, which may prevent them from undergoing transplantation. Therefore, up-front allo-SCT is an option, particularly for patients with life-threatening cytopenias. In the absence of prospective randomized trials, the main therapeutic approaches are discussed in this review.

  12. The lung function score and its components as predictors of overall survival and chronic graft-vs-host disease after allogeneic stem cell transplantation

    PubMed Central

    Ditz, Diana; Rabanus, Robert; Schulz, Christian; Wolff, Daniel; Holler, Barbara; Holler, Ernst; Hildebrandt, Gerhard Carl

    2016-01-01

    Aim To retrospectively assess if the modified lung function score (LFS) and/or its components, forced expiratory volume within the first second (FEV1) and diffusion capacity for carbon monoxide corrected for hemoglobin level (cDLCO), predict overall survival (OS) and chronic graft-vs-host-disease (cGvHD). Methods We evaluated 241 patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the University of Regensburg Transplant Center between June 1998 and July 2005 in relation to their LFS, FEV1 and cDLCO, before and after HSCT. Results Decreased OS after allo-HSCT was related to decreased pre-transplantation values of FEV1<60% (P = 0.040), cDLCO<50% of predicted value (P = 0.025), and LFS≥III (P = 0.037). It was also related to decreased FEV1 at 3 and 12 months after HSCT (P < 0.001 and P = 0.001, respectively) and increased LFS at 3 and 12 months after HSCT (P = 0.028 and P = 0.002, respectively), but not to changes of cDLCO. A higher incidence of cGvHD was related to decreased FEV1 at 6, 12, and 18 months (P = 0.069, P = 0.054, and P = 0.009, respectively) and increased LFS at 12 months (P = 0.002), but not to changes in cDLCO. Conclusions OS was related to both LFS and FEV1, but cGvHD had a stronger relation to FEV1 than to cDLCO or LFS. FEV1 alone offered more information on the outcome after allo-HSCT than LFS or cDLCO, suggesting limited value of LFS for the patients’ assessment after allo-HSCT. PMID:26935611

  13. Rituximab, fludarabine, and total body irradiation as conditioning regimen before allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia: long-term prospective multicenter study.

    PubMed

    Michallet, Mauricette; Socié, Gerard; Mohty, Mohamad; Sobh, Mohamad; Bay, Jacques-O; Morisset, Stéphane; Labussière-Wallet, Hélène; Tabrizi, Reza; Milpied, Noel; Bordigoni, Pierre; El-Cheikh, Jean; Blaise, Didier

    2013-02-01

    To evaluate the efficacy and toxicity of reduced-intensity conditioning (RIC) combining fludarabine, low-dose total body irradiation (TBI) and rituximab before allogeneic hematopoietic stem cell transplantation (allo-HSCT) from human leucocyte antigen (HLA) identical siblings, we conducted a prospective study in patients ≤65 years old with advanced chronic lymphocytic leukemia (CLL) stage B or C in response after a salvage treatment. Conditioning included rituximab (375 mg/m² on day 5), fludarabine (30 mg/m² from day 4 to day 2), TBI (2 Gy on day 0), and rituximab (500 mg/m² on days 1 and 8). Forty patients were included, 34 (85%) were male with a median age of 54 years (range, 35-65 years), 38 (95%) were in B stage, and 2 were in stage C; only 7 patients (17%) were in complete response. Seven (17%) patients did not receive rituximab. Thirty-nine (98%) patients engrafted, 17 patients developed acute graft-versus-host disease (GVHD) grade ≥II with a cumulative incidence at 3 months of 44% (36-52) with a significant protective effect of rituximab (p = 0.02). The cumulative incidence of chronic GVHD was 29% (21-36) at 12 months for both limited and extensive forms. The median overall survival was not reached with 5-years probability of 55% (41-74). The multivariate analysis showed a positive effect of rituximab on overall survival and event-free survival (hazard ratio [HR] = 0.1 [0-0.6], p = 0.02; and HR = 0.1 [0-0.4], p = 0.035, respectively). The association of fludarabine, TBI, and rituximab is feasible, well tolerated, and allows better outcomes in advanced CLL.

  14. Posaconazole oral suspension primary prophylaxis in acute leukemia and allogeneic stem cell transplant patients: can it be used without measurement of plasma concentration?

    PubMed

    Girmenia, Corrado; Annino, Luciana; Mariotti, Benedetta; Fanci, Rosa; Minotti, Clara; Spadea, Antonio; Carotti, Alessandra; Piedimonte, Monica; Chierichini, Anna; Cerchiara, Elisabetta; Caselli, Desiree; Cupelli, Luca; Arcioni, Francesco; Bertaina, Alice; Ribersani, Michela; Proia, Anna; Mengarelli, Andrea; Perriello, Vincenzo; Torelli, Giovanni Fernando; Di Gioia, Massimo; Del Principe, Maria Ilaria; Cassetta, Maria Iris; Fallani, Stefania; Novelli, Andrea

    2016-07-01

    Posaconazole oral suspension (PCZ-susp) can display a variable degree of inter and intra-individual absorption. However, there is no agreement on the need of plasma-posaconazole-concentration (PPC) monitoring as a routine practice in patients receiving PCZ-susp. In this prospective, multicenter study we evaluated the variability of PPCs in hematologic patients receiving PCZ-susp prophylaxis with the aim to define conditions at different risk of subtherapeutic PPCs. Overall, 103 acute leukemia (AL) patients submitted to intensive chemotherapy (115 courses) and 46 allogeneic stem cell transplant (allo-SCT) recipients (47 courses) receiving PCZ-susp prophylaxis were considered. The adequacy of PPC pattern after the steady state (≥day 7 of treatment) in courses with two or more PPC measurements was defined as follows: inadequate pattern: PPC < 0.5 mcg/ml at least once; borderline pattern: PPC always ≥0.5mcg/ml but < 0.7 mcg/ml at least once; adequate pattern: PPC always ≥0.7 mcg/ml. The PPC pattern was evaluable in 83 and 37 AL and allo-SCT patients, respectively. It was adequate, borderline and inadequate in 63.9%, 14.5%, and 21.7% of courses, respectively, in AL, and in 62.2%, 10.8%, and 27.0% of courses, respectively, in allo-SCT. In both groups, an inadequate PPC pattern was associated with the development of diarrhea. In absence of diarrhea, the probability of an inadequate PPC pattern was 11.9% in AL and 17.2% in allo-SCT patients. PCZ-susp might be used without stringent need of PPC monitoring in patients without diarrhea.

  15. Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia.

    PubMed

    Aoki, Jun; Kanamori, Heiwa; Tanaka, Masatsugu; Yamasaki, Satoshi; Fukuda, Takahiro; Ogawa, Hiroyasu; Iwato, Koji; Ohashi, Kazuteru; Okumura, Hirokazu; Onizuka, Makoto; Maesako, Yoshitomo; Teshima, Takanori; Kobayashi, Naoki; Morishima, Yasuo; Hirokawa, Makoto; Atsuta, Yoshiko; Yano, Shingo; Takami, Akiyoshi

    2016-03-01

    Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large-scale, nationwide retrospective study to examine the impact of age on outcomes of allo-HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50-54, 249 patients (32.9%) were 55-59, 301 patients (39.8%) were 60-64 and 118 patients (15.6%) were ≥65 years old. The 3-year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo-HSCT in elderly AML patients. PMID:26663096

  16. Allogeneic Hematopoietic Stem Cell Transplantation after Conditioning Regimens with Fludarabine/melphalan or Fludarabine/busulfan for Patients with Hematological Malignancies: A Single-center Analysis.

    PubMed

    Yamamoto, Wataru; Andou, Taiki; Itabashi, Megumi; Koyama, Satoshi; Ishii, Yoshimi; Numata, Ayumi; Motohashi, Kenji; Hagihara, Maki; Matsumoto, Kenji; Fujisawa, Shin

    2016-01-01

    Objective Fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) are two major conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods We retrospectively analyzed patients who underwent allo-HSCT after a conditioning regimen consisting of FM or FB with/without total body irradiation for hematological malignancies between 2005 and 2014. Results There were 41 patients who met the criteria. The median follow-up time for the survivors was 3 years. Thirty-two patients received allo-HSCT after the FM regimen and nine patients received allo-HSCT after the FB regimen. Patients who received FB were older than those who received FM (p=0.041). There was no significant difference in the 3-year overall survival between patients who had received FB and those who had received FM (29.6% vs. 56.5%, p=0.267). The 3-year cumulative incidence of relapse was significantly higher in patients who had received FB than that in patients who had received FM (66.7% vs. 17.8%, p=0.004), and FB was an independent prognostic factor for relapse by a multivariate analysis (hazard ratio, 9.8; 95% confidential interval, 2.5-39.3; p=0.001). When we restricted the evaluation to patients with acute myeloid leukemia and myelodysplastic syndrome, the 3-year cumulative incidence of relapse was also significantly higher in patients who had received FB than that in patients who had received FM (75.0% vs. 16.1%, p=0.004). Conclusion The results suggest that FM may provide better disease control than FB.

  17. Zone-specific integrated cartilage repair using a scaffold-free tissue engineered construct derived from allogenic synovial mesenchymal stem cells: Biomechanical and histological assessments.

    PubMed

    Fujie, Hiromichi; Nansai, Ryosuke; Ando, Wataru; Shimomura, Kazunori; Moriguchi, Yu; Hart, David A; Nakamura, Norimasa

    2015-11-26

    The purpose of the present study was to investigate the zone-specific integration properties of articular cartilage defects treated in vivo with scaffold-free three-dimensional tissue-engineered constructs (TECs) derived from allogenic synovial mesenchymal stem cells (MSCs) in a porcine model. The TEC derived from the synovial MSCs was implanted into chondral defects in the medial femoral condyle of the knee. The integration boundary of repair tissue with the adjacent host cartilage was morphologically and biomechanically evaluated at 6 months post-implantation. Histological assessments showed that the repair tissue in each zone was well integrated with the adjacent host cartilage, with an apparent secure continuity of the extracellular matrix. There were no significant differences in histological scores between the integration boundary and the center of the repair tissue at every zone. Nonetheless, in all the specimens subjected to mechanical testing, failure occurred at the integration boundary. The average tensile strength of the integration boundary vs normal cartilage was 0.6 vs 4.9, 3.0 vs 12.6, and 5.5 vs 12.8MPa at the superficial, middle, and deep layers, respectively. Thus, these results indicate the most fragile point in the repair tissue remained at the integration boundary in spite of the apparent secure tissue continuity and equivalent histological quality with the center of the repair tissue. Such tissue vulnerability at the surface integration boundary could affect the long-term durability of the tissue repair, and thus, special consideration will be needed in the post-operative rehabilitation programming to enhance the longevity of such repair tissues in response to normal knee loading.

  18. Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation.

    PubMed

    Lim, Ji-Young; Ryu, Da-Bin; Lee, Sung-Eun; Park, Gyeongsin; Choi, Eun Young; Min, Chang-Ki

    2015-11-01

    Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 (H-2(b)) → B6D2F1 (H-2(b/d)), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type (H-2(d)) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-γ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-γ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT.

  19. Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation - A comparison of the last two decades.

    PubMed

    Svenberg, Petter; Remberger, Mats; Uzunel, Mehmet; Mattsson, Jonas; Gustafsson, Britt; Fjaertoft, Gustav; Sundin, Mikael; Winiarski, Jacek; Ringdén, Olle

    2016-08-01

    Pediatric protocols for allogeneic hematopoietic SCT have been altered during the last two decades. To compare the outcomes in children (<18 yr old), who underwent SCT at our center during 1992-2002 (P1) and 2003-2013 (P2). We retrospectively analyzed 188 patients in P1 and 201 patients in P2. The most significant protocol changes during P2 compared with P1 were a decrease in MAC protocols, particularly those containing TBI, an increase in RIC protocols, and altered GvHD prophylaxis. In addition, P2 had more patients with nonmalignant diagnoses (p = 0.002), more mismatched (MM) donors (p = 0.01), and more umbilical CB grafts (p = 0.03). Mesenchymal or DSCs were used for severe acute GvHD during P2. Three-yr OS in P1 was 58%, and in P2, it was 78% (p < 0.001). Improved OS was seen in both malignant disorders (51% vs. 68%; p = 0.05) and nonmalignant disorders (77% vs. 87%; p = 0.04). Multivariate analysis showed that SCT during P2 was associated with reduced mortality (HR = 0.57; p = 0.005), reduced TRM (HR = 0.57; p = 0.03), unchanged relapse rate, similar rate of GF, less chronic GvHD (HR = 0.49; p = 0.01), and more acute GvHD (HR = 1.77, p = 0.007). During recent years, OS has improved at our center, possibly reflecting the introduction of less toxic conditioning regimens and a number of other methodological developments in SCT. PMID:27251184

  20. Mediastinal Germ Cell Tumor-associated Histiocytic Proliferations Treated With Thalidomide Plus Chemotherapy Followed by Alemtuzumab-containing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation: A Case Report.

    PubMed

    Fang, Li-Hua; Shih, Li-Sun; Lee, Pei-Ing; Chen, Wei-Ting; Chen, Rong-Long

    2016-01-01

    Mediastinal nonseminomatous germ cell tumor (MNSGCT)-associated histiocytic proliferations are rare and rapidly fatal disorders. Standard treatment modalities have yet to be established.We report a case of MNSGCT-associated hemophagocytic syndrome that evolved into malignant histiocytosis/disseminated histiocytic sarcoma (MH/HS), which was initially treated with intravenous immunoglobulin, corticosteroids, and cyclosporine. Then, thalidomide plus cyclophosphamide, adriamycin, oncovin, prednisolone chemotherapy followed by alemtuzumab-containing reduced-intensity allogeneic peripheral blood stem cell transplantation (PBSCT) was used as salvage therapy.The severe constitutional symptoms and pancytopenia resolved shortly after thalidomide with cyclophosphamide, adriamycin, oncovin, prednisolone. After PBSCT, the patient developed steroid-dependent skin graft-versus-host disease, but maintained a functional life for 1.5 years. Rapid resolution of chronic graft-versus-host disease preceded the fulminant recurrence of hemophagocytic syndrome and MH/HS.Thalidomide plus chemotherapy followed by alemtuzumab-containing reduced intensity allogeneic PBSCT is effective in allaying MNSGCT-associated histiocytic disorders, but does not prevent eventual relapse. However, further posttransplant immune modulation should be developed to completely eradicate the residual MH/HS cells.

  1. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty

    PubMed Central

    Golpanian, Samuel; DiFede, Darcy L.; Pujol, Marietsy V.; Lowery, Maureen H.; Levis-Dusseau, Silvina; Goldstein, Bradley J.; Schulman, Ivonne H.; Longsomboon, Bangon; Wolf, Ariel; Khan, Aisha; Heldman, Alan W.; Goldschmidt-Clermont, Pascal J.; Hare, Joshua M.

    2016-01-01

    Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty. PMID:26933813

  2. Uveitis and Myositis as Immune Complications in Chemorefractory NK/T-Cell Nasal-Type Lymphoma Successfully Treated with Allogeneic Stem-Cell Transplant

    PubMed Central

    Gómez-Crespo, Maria José; López-Lorenzo, Jose Luis; Villaescusa, Teresa; Rodríguez-Pinilla, María; Fortes, José; Serrano, Cristina; Machan, Salma; Llamas, Pilar; Córdoba, Raúl

    2016-01-01

    NK/T-cell lymphomas are a group of clonal proliferations of NK- or, rarely, T-cell types and have peculiar clinicopathologic features. Most common site of involvement is the upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses, and palate). Association of autoimmune paraneoplastic disorders with NK/T-cell lymphomas is not well studied. Our patient was diagnosed with NK/T-cell lymphoma stage IV with skin involvement and treated frontline with CHOEP regimen. While he was under treatment, two immune complications presented: anterior uveitis of autoimmune origin refractory to steroids and myositis in lower limbs muscles. Autologous transplantation was rejected due to confirmed early relapse after first-line treatment, and the patient received second-line treatment according to the SMILE scheme, reaching complete response after four cycles. The patient underwent allogeneic transplantation and at the time of manuscript preparation is alive despite multiple complications. The disease should be suspected in patients with rhinitis or recurrent sinusitis, and early biopsy is recommended for all patients to avoid a delay in diagnosis. Our patient also presented symptoms of disease progression after first-line treatment, representing a paraneoplastic process, a very rare phenomenon in T-type lymphomas. This case is novel for the appearance of an inflammatory myositis, a histologically verified paraneoplastic phenomenon that responded to treatment for lymphoma. PMID:27807488

  3. Clinical factors influencing phenotype of HCMV-specific CD8+ T cells and HCMV-induced interferon-gamma production after allogeneic stem cells transplantation.

    PubMed

    Gayoso, Inmaculada; Cantisán, Sara; Cerrato, Carolina; Sánchez-García, Joaquín; Martin, Carmen; Solana, Rafael; Torres-Gomez, Antonio; Torre-Cisneros, Julian

    2013-01-01

    Human cytomegalovirus (HCMV) infection causes significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). In this work, we characterized the phenotype and interferon-gamma (INF-γ) production of HCMV-specific T cells using QuantiFERON-HCMV assay in 26 patients 6 months after HSCT. We analysed whether these two parameters were associated with clinical variables. Our results showed that the patients receiving stem cells from donors ≥40 years old were 12 times more likely to have HCMV-specific CD8+ T cells with "differentiated phenotype" (CD45RA+CCR7+ ≤6.7% and CD28+ ≤30%) than patients grafted from donors <40 years old (OR = 12; P = 0.014). In addition, a detectable IFN-γ production in response to HCMV peptides (cutoff 0.2 IU/mL IFN-γ; "reactive" QuantiFERON-HCMV test) was statistically associated with HCMV replication after transplantation (OR = 11; P = 0.026), recipients ≥40 versus <40 years old (OR = 11; P = 0.026), and the use of peripheral blood versus bone marrow as stem cell source (OR = 17.5; P = 0.024). In conclusion, donor age is the only factor significantly associated with the presence of the "differentiated phenotype" in HCMV-specific CD8+ T cells, whereas HCMV replication after transplantation, recipient age, and stem cell source are the factors associated with the production of IFN-γ in response to HCMV epitopes.

  4. Impact of pre-transplant pulmonary infection developed in horizontal laminar flow unit on the outcome of subsequent allogeneic hematopoietic stem cell transplantation

    PubMed Central

    He, Gan-Lin; Chang, Ying-Jun; Xu, Lan-Ping; Zhang, Xiao-Hui; Wang, Yu; Liu, Kai-Yan

    2016-01-01

    Background So far, there is very little literature on how pre-transplant pulmonary infection developed in horizontal laminar flow unit (HLFU) affects outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A retrospective analysis was performed on allo-HSCT recipients who were diagnosed with pre-transplant pulmonary infection developed in HLFU between January 2012 and December 2012. Various tests were analyzed to evaluate the overall survival (OS) and pulmonary infection rate after allo-HSCT. Results Among 317 patients who received allo-HSCT from related donors, 7 cases of human leukocyte antigen (HLA)-haploidentical transplantation reported a fever, cough, and other symptoms before transplantation. Chest radiography findings showed pulmonary infection, and the C-reactive protein (CRP) level was higher than normal, which confirmed pulmonary infection (incidence rate 2.21%). The Breslow test suggested that the early survival rate was lower in the group with pre-transplant pulmonary infection than in the group without pre-transplant pulmonary infection (OS: 28.4 vs. 42.4 months; P=0.023); the early survival rate was lower in patients with a pulmonary infection accompanied by bilateral pleural effusion than in patients without pleural effusion (OS: 1.5 vs. 36.3 months; P=0.010). In the first month after transplantation, the difference in the CD4CD45RO+CD45RA- and CD4CD45RO-CD45RA+ between the groups with and without pre-transplant pulmonary infection was statistically significant (P<0.05). Patients with pre-transplant pulmonary infection who survived >3 years had a higher rate of pulmonary infection in the first 2 months after allo-HSCT than those without pre-transplant pulmonary infection [100% (5/5 patients) vs. 38.1% (118/310); χ2=5.542, P=0.019]. Conclusions Development of pre-transplant pulmonary infection in the HLFU in patients with hematological malignancies who receive HLA-haploidentical HSCT is associated with an increased risk

  5. The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients with Mixed Lineage Leukemia (MLL) Rearrangements

    PubMed Central

    Yang, Hua; Huang, Sai; Zhu, Cheng-Ying; Gao, Li; Zhu, Hai-Yan; Lv, Na; Jing, Yu; Yu, Li

    2016-01-01

    Background Acute myeloid leukemia (AML) patients with mixed lineage leukemia (MLL) gene rearrangements always had a very poor prognosis. In this study, we report the incidence of MLL rearrangements in AML patients using gene analysis, as well as the clinical significance and prognostic features of these rearrangements. Material/Methods This retrospective study took place from April 2008 to November 2011 in the People’s Liberation Army General Hospital. A total 433 AML patients were screened by multiple nested reverse transcription polymerase chain reaction (RT-PCR) to determine the incidence of the 11 MLL gene rearrangements. There were 68 cases of MLL gene rearrangements, for a positive rate of 15.7%. A total of 24 patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and 34 patients received at least 4 cycles of chemotherapy. Ten patients were lost to follow-up. Results The median follow-up was 29 months. The complete remission (CR) rate was 85.4%. The overall survival (OS) was 57.4±5.9 months for the Allo-HSCT group and 21.0±2.1 months for the chemotherapy group. The Allo-HSCT group had superior survival compared with the chemotherapy group (5-year OS: 59±17% vs. 13±8%, P<0.01; 5-year disease-free survival [DFS]: 65±10% vs. 40±16%, P>0.05). Multivariate analysis showed that transplantation, platelets >50×109/L at onset, and CR are associated with a better OS in MLL rearranged AML patients. Patients with thrombocytopenia and extramedullary involvement were prone to relapse. Conclusions Our results suggest that Allo-HSCT is superior to chemotherapy alone for treating MLL rearranged AML patients. Patients treated with Allo-HSCT have a better prognosis and a longer survival. CR is an independent prognostic factor for OS, and extramedullary involvement is an independent prognostic factor for DFS. MLL rearranged AML patients with thrombocytopenia at onset <50×109 had very bad OS and DFS. PMID:27373985

  6. Impact of pre-transplant pulmonary infection developed in horizontal laminar flow unit on the outcome of subsequent allogeneic hematopoietic stem cell transplantation

    PubMed Central

    He, Gan-Lin; Chang, Ying-Jun; Xu, Lan-Ping; Zhang, Xiao-Hui; Wang, Yu; Liu, Kai-Yan

    2016-01-01

    Background So far, there is very little literature on how pre-transplant pulmonary infection developed in horizontal laminar flow unit (HLFU) affects outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A retrospective analysis was performed on allo-HSCT recipients who were diagnosed with pre-transplant pulmonary infection developed in HLFU between January 2012 and December 2012. Various tests were analyzed to evaluate the overall survival (OS) and pulmonary infection rate after allo-HSCT. Results Among 317 patients who received allo-HSCT from related donors, 7 cases of human leukocyte antigen (HLA)-haploidentical transplantation reported a fever, cough, and other symptoms before transplantation. Chest radiography findings showed pulmonary infection, and the C-reactive protein (CRP) level was higher than normal, which confirmed pulmonary infection (incidence rate 2.21%). The Breslow test suggested that the early survival rate was lower in the group with pre-transplant pulmonary infection than in the group without pre-transplant pulmonary infection (OS: 28.4 vs. 42.4 months; P=0.023); the early survival rate was lower in patients with a pulmonary infection accompanied by bilateral pleural effusion than in patients without pleural effusion (OS: 1.5 vs. 36.3 months; P=0.010). In the first month after transplantation, the difference in the CD4CD45RO+CD45RA- and CD4CD45RO-CD45RA+ between the groups with and without pre-transplant pulmonary infection was statistically significant (P<0.05). Patients with pre-transplant pulmonary infection who survived >3 years had a higher rate of pulmonary infection in the first 2 months after allo-HSCT than those without pre-transplant pulmonary infection [100% (5/5 patients) vs. 38.1% (118/310); χ2=5.542, P=0.019]. Conclusions Development of pre-transplant pulmonary infection in the HLFU in patients with hematological malignancies who receive HLA-haploidentical HSCT is associated with an increased risk

  7. Systemic Delivery of Allogenic Muscle Stem Cells Induces Long-Term Muscle Repair and Clinical Efficacy in Duchenne Muscular Dystrophy Dogs

    PubMed Central

    Rouger, Karl; Larcher, Thibaut; Dubreil, Laurence; Deschamps, Jack-Yves; Le Guiner, Caroline; Jouvion, Gregory; Delorme, Bruno; Lieubeau, Blandine; Carlus, Marine; Fornasari, Benoît; Theret, Marine; Orlando, Priscilla; Ledevin, Mireille; Zuber, Céline; Leroux, Isabelle; Deleau, Stéphane; Guigand, Lydie; Testault, Isabelle; Le Rumeur, Elisabeth; Fiszman, Marc; Chérel, Yan

    2011-01-01

    Duchenne muscular dystrophy (DMD) is a genetic progressive muscle disease resulting from the lack of dystrophin and without effective treatment. Adult stem cell populations have given new impetus to cell-based therapy of neuromuscular diseases. One of them, muscle-derived stem cells, isolated based on delayed adhesion properties, contributes to injured muscle repair. However, these data were collected in dystrophic mice that exhibit a relatively mild tissue phenotype and clinical features of DMD patients. Here, we characterized canine delayed adherent stem cells and investigated the efficacy of their systemic delivery in the clinically relevant DMD animal model to assess potential therapeutic application in humans. Delayed adherent stem cells, named MuStem cells (muscle stem cells), were isolated from healthy dog muscle using a preplating technique. In vitro, MuStem cells displayed a large expansion capacity, an ability to proliferate in suspension, and a multilineage differentiation potential. Phenotypically, they corresponded to early myogenic progenitors and uncommitted cells. When injected in immunosuppressed dystrophic dogs, they contributed to myofiber regeneration, satellite cell replenishment, and dystrophin expression. Importantly, their systemic delivery resulted in long-term dystrophin expression, muscle damage course limitation with an increased regeneration activity and an interstitial expansion restriction, and persisting stabilization of the dog's clinical status. These results demonstrate that MuStem cells could provide an attractive therapeutic avenue for DMD patients. PMID:21924229

  8. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease.

    PubMed

    Holler, Ernst; Butzhammer, Peter; Schmid, Karin; Hundsrucker, Christian; Koestler, Josef; Peter, Katrin; Zhu, Wentao; Sporrer, Daniela; Hehlgans, Thomas; Kreutz, Marina; Holler, Barbara; Wolff, Daniel; Edinger, Matthias; Andreesen, Reinhard; Levine, John E; Ferrara, James L; Gessner, Andre; Spang, Rainer; Oefner, Peter J

    2014-05-01

    Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.

  9. Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation.

    PubMed

    Sobecks, R M; Ball, E J; Askar, M; Theil, K S; Rybicki, L A; Thomas, D; Brown, S; Kalaycio, M; Andresen, S; Pohlman, B; Dean, R; Sweetenham, J; Macklis, R; Bernhard, L; Cherni, K; Copelan, E; Maciejewski, J P; Bolwell, B J

    2008-04-01

    Achievement of complete donor chimerism (CDC) after allogeneic nonmyeloablative hematopoietic stem cell transplantation (NMHSCT) is important for preventing graft rejection and for generating a graft-vs-malignancy effect. The alloreactivity of NK cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors (KIRs) with target cell HLA/KIR ligands. The influence of KIR matching on the achievement of T-cell CDC after NMHSCT has not been previously described. We analyzed 31 patients undergoing T-cell replete related donor NMHSCT following fludarabine and 200 cGy TBI. Recipient inhibitory KIR genotype and donor HLA/KIR ligand matches were used to generate an inhibitory KIR score from 1 to 4 based upon the potential number of recipient inhibitory KIRs that could be engaged with donor HLA/KIR ligands. Patients with a score of 1 were less likely to achieve T-cell CDC (P=0.016) and more likely to develop graft rejection (P=0.011) than those with scores greater than 1. Thus, patients with lower inhibitory KIR scores may have more active anti-donor immune effector cells that may reduce donor chimerism. Conversely, patients with greater inhibitory KIR scores may have less active NK cell and T-cell populations, which may make them more likely to achieve CDC.

  10. Allogeneic Platelet Releasate Preparations Derived via a Novel Rapid Thrombin Activation Process Promote Rapid Growth and Increased BMP-2 and BMP-4 Expression in Human Adipose-Derived Stem Cells

    PubMed Central

    McLaughlin, Michael; Gagnet, Paul; Cunningham, Elizabeth; Yeager, Randi; D'Amico, Michael; Guski, Katie; Scarpone, Michael; Kuebler, Daniel

    2016-01-01

    The administration of human adipose-derived stem cells (ASCs) represents a promising regenerative therapy for the treatment of orthopedic injuries. While ASCs can be easily isolated from liposuction-derived adipose tissue, most clinical applications will likely require in vitro culture expansion of these cells using nonxenogeneic components. In this study, platelet releasate was generated using a novel rapid thrombin activation method (tPR). ASCs grown in media supplemented with tPR proliferated much faster than ASCs grown in media supplemented with 10% fetal bovine serum. The cells also retained the ability to differentiate along chondrogenic, adipogenic, and osteogenic lineages. The tPR cultured ASCs displayed elevated expression of BMP-4 (5.7 ± 0.97-fold increase) and BMP-2 (4.7 ± 1.3-fold increase) and decreased expression of PDGF-B (4.0 ± 1.4-fold decrease) and FGF-2 (33 ± 9.0-fold decrease). No significant changes in expression were seen with TGF-β and VEGF. This pattern of gene expression was consistent across different allogeneic tPR samples and different ASC lines. The use of allogeneic rapidly activated tPR to culture ASCs is associated with both an increased cell yield and a defined gene expression profile making it an attractive option for cell expansion prior to cell-based therapy for orthopedic applications. PMID:26823671

  11. Allogeneic Platelet Releasate Preparations Derived via a Novel Rapid Thrombin Activation Process Promote Rapid Growth and Increased BMP-2 and BMP-4 Expression in Human Adipose-Derived Stem Cells.

    PubMed

    McLaughlin, Michael; Gagnet, Paul; Cunningham, Elizabeth; Yeager, Randi; D'Amico, Michael; Guski, Katie; Scarpone, Michael; Kuebler, Daniel

    2016-01-01

    The administration of human adipose-derived stem cells (ASCs) represents a promising regenerative therapy for the treatment of orthopedic injuries. While ASCs can be easily isolated from liposuction-derived adipose tissue, most clinical applications will likely require in vitro culture expansion of these cells using nonxenogeneic components. In this study, platelet releasate was generated using a novel rapid thrombin activation method (tPR). ASCs grown in media supplemented with tPR proliferated much faster than ASCs grown in media supplemented with 10% fetal bovine serum. The cells also retained the ability to differentiate along chondrogenic, adipogenic, and osteogenic lineages. The tPR cultured ASCs displayed elevated expression of BMP-4 (5.7 ± 0.97-fold increase) and BMP-2 (4.7 ± 1.3-fold increase) and decreased expression of PDGF-B (4.0 ± 1.4-fold decrease) and FGF-2 (33 ± 9.0-fold decrease). No significant changes in expression were seen with TGF-β and VEGF. This pattern of gene expression was consistent across different allogeneic tPR samples and different ASC lines. The use of allogeneic rapidly activated tPR to culture ASCs is associated with both an increased cell yield and a defined gene expression profile making it an attractive option for cell expansion prior to cell-based therapy for orthopedic applications.

  12. Short Course of Post-Transplantation Cyclophosphamide and Bortezomib for Graft-versus-Host Disease Prevention after Allogeneic Peripheral Blood Stem Cell Transplantation Is Feasible and Yields Favorable Results: A Phase I Study.

    PubMed

    Al-Homsi, Ahmad-Samer; Cole, Kelli; Bogema, Marlee; Duffner, Ulrich; Williams, Stephanie; Mageed, Aly

    2015-07-01

    An effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells. It has been successfully used to prevent GVHD after allogeneic HSCT. Bortezomib has antitumor activity on a variety of hematological malignancies and exhibits a number of favorable immunomodulatory effects that include inhibition of dendritic cells. Therefore, an approach that combines post-transplantation cyclophosphamide and bortezomib seems attractive. Herein, we report the results of a phase I study examining the feasibility and safety of high-dose post-transplantation cyclophosphamide in combination with bortezomib in patients undergoing allogeneic peripheral blood HSCT from matched siblings or unrelated donors after reduced-intensity conditioning. Cyclophosphamide was given at a fixed dose (50 mg/kg on days +3 and +4). Bortezomib dose was started at .7 mg/m2, escalated up to 1.3 mg/m2, and was administered on days 0 and +3. Patients receiving grafts from unrelated donors also received rabbit antithymocyte globulin. The combination was well tolerated and allowed prompt engraftment in all patients. The incidences of acute GVHD grades II to IV and grades III and IV were 20% and 6.7%, respectively. With a median follow-up of 9.1 months (range, 4.3 to 26.7), treatment-related mortality was 13.5% with predicted 2-year disease-free survival and overall survival of 55.7% and 68%, respectively. The study suggests that the combination of post-transplantation cyclophosphamide and bortezomib is feasible and may offer an effective and practical GVHD prophylactic

  13. Clinical Factors Influencing Phenotype of HCMV-Specific CD8+ T Cells and HCMV-Induced Interferon-Gamma Production after Allogeneic Stem Cells Transplantation

    PubMed Central

    Cantisán, Sara; Cerrato, Carolina; Sánchez-García, Joaquín; Martin, Carmen; Solana, Rafael; Torres-Gomez, Antonio; Torre-Cisneros, Julian

    2013-01-01

    Human cytomegalovirus (HCMV) infection causes significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). In this work, we characterized the phenotype and interferon-gamma (INF-γ) production of HCMV-specific T cells using QuantiFERON-HCMV assay in 26 patients 6 months after HSCT. We analysed whether these two parameters were associated with clinical variables. Our results showed that the patients receiving stem cells from donors ≥40 years old were 12 times more likely to have HCMV-specific CD8+ T cells with “differentiated phenotype” (CD45RA+CCR7+ ≤6.7% and CD28+ ≤30%) than patients grafted from donors <40 years old (OR = 12; P = 0.014). In addition, a detectable IFN-γ production in response to HCMV peptides (cutoff 0.2 IU/mL IFN-γ; “reactive” QuantiFERON-HCMV test) was statistically associated with HCMV replication after transplantation (OR = 11; P = 0.026), recipients ≥40 versus <40 years old (OR = 11; P = 0.026), and the use of peripheral blood versus bone marrow as stem cell source (OR = 17.5; P = 0.024). In conclusion, donor age is the only factor significantly associated with the presence of the “differentiated phenotype” in HCMV-specific CD8+ T cells, whereas HCMV replication after transplantation, recipient age, and stem cell source are the factors associated with the production of IFN-γ in response to HCMV epitopes. PMID:23424600

  14. Blood-Forming Stem Cell Transplants

    MedlinePlus

    ... Health Professionals Questions to Ask about Your Treatment Research Blood-Forming Stem Cell Transplants On This Page What are bone marrow ... are evaluating BMT and PBSCT in clinical trials (research studies) for the treatment ... are the donor’s stem cells matched to the patient’s stem cells in allogeneic ...

  15. Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation

    PubMed Central

    Lim, Ji-Young; Ryu, Da-Bin; Lee, Sung-Eun; Park, Gyeongsin; Choi, Eun Young; Min, Chang-Ki

    2015-01-01

    Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 (H-2b) → B6D2F1 (H-2b/d), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type (H-2d) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-γ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-γ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT. PMID:26552489

  16. Homing of allogeneic nestin-positive hair follicle-associated pluripotent stem cells after maternal transplantation in experimental model of cortical dysplasia.

    PubMed

    Omidi, Ameneh; Kashani, Iraj Ragerdi; Akbari, Mohammad; Mortezaee, Keywan; Ghasemi, Soudabeh; Beyer, Cordian; Zendedel, Adib

    2015-12-01

    An embryo has the capability to accept allo- or xeno-geneic cells, which probably makes it an ideal candidate for stem cell transplantation of various cerebral cortex abnormalities, such as cortical dysplasia. The aim of this study was to determine hair follicle-associated pluripotent (HAP) stem cells homing into various organs of mother and fetus. Cells were obtained, analyzed for immunophenotypic features, and then labelled with CM-Dil; nestin(+)HAP stem cells or media phosphate-buffered saline (PBS) were intravenously delivered on day 16 of gestation in BALB/c mice, which intraperitoneally received methylazoxymethanol (MAM) one day in advance, and homing was assessed at 24 h after cell injection. Flow cytometry and immunocytochemistry manifested positive expression of nestin in HAP stem cells. For both mother and fetus, brain, lungs, liver, and spleen were the host organs for cell implants. For the brain, the figure was considerably higher in fetus, 4.05 ± 0.5% (p ≤ 0.05 vs. mother). MAM-injected mice had a downward trend for SDF-1α and CXCR4 (p ≤ 0.05 vs. control), but HAP stem cells group showed an upward trend for CXCR4 (p ≤ 0.05 vs. MAM). We conclude the HAP stem cells show homing potential in experimental cortical dysplasia, which may permit these cells to be a target in future work on prenatal therapy of neural disorders. PMID:26568364

  17. Homing of allogeneic nestin-positive hair follicle-associated pluripotent stem cells after maternal transplantation in experimental model of cortical dysplasia.

    PubMed

    Omidi, Ameneh; Kashani, Iraj Ragerdi; Akbari, Mohammad; Mortezaee, Keywan; Ghasemi, Soudabeh; Beyer, Cordian; Zendedel, Adib

    2015-12-01

    An embryo has the capability to accept allo- or xeno-geneic cells, which probably makes it an ideal candidate for stem cell transplantation of various cerebral cortex abnormalities, such as cortical dysplasia. The aim of this study was to determine hair follicle-associated pluripotent (HAP) stem cells homing into various organs of mother and fetus. Cells were obtained, analyzed for immunophenotypic features, and then labelled with CM-Dil; nestin(+)HAP stem cells or media phosphate-buffered saline (PBS) were intravenously delivered on day 16 of gestation in BALB/c mice, which intraperitoneally received methylazoxymethanol (MAM) one day in advance, and homing was assessed at 24 h after cell injection. Flow cytometry and immunocytochemistry manifested positive expression of nestin in HAP stem cells. For both mother and fetus, brain, lungs, liver, and spleen were the host organs for cell implants. For the brain, the figure was considerably higher in fetus, 4.05 ± 0.5% (p ≤ 0.05 vs. mother). MAM-injected mice had a downward trend for SDF-1α and CXCR4 (p ≤ 0.05 vs. control), but HAP stem cells group showed an upward trend for CXCR4 (p ≤ 0.05 vs. MAM). We conclude the HAP stem cells show homing potential in experimental cortical dysplasia, which may permit these cells to be a target in future work on prenatal therapy of neural disorders.

  18. Ongoing graft-versus-host disease is a risk factor for azoospermia after allogeneic hematopoietic stem cell transplantation: a survey of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation

    PubMed Central

    Rovó, Alicia; Aljurf, Mahmoud; Chiodi, Sandra; Spinelli, Simonetta; Salooja, Nina; Sucak, Gülsan; Hunter, Ann; Kim, Tan Swee; Socié, Gérard; van Lint, Maria Teresa; Passweg, Jakob R.; Arat, Mutlu; Badoglio, Manuela; Tichelli, André

    2013-01-01

    The aim of this study was to assess the degree of spermatogenesis defects in sperm analysis in long-term male survivors after allogeneic hematopoietic stem cell transplantation in order to identify the risk factors related to potential infertility after hematopoietic stem cell transplantation and to provide data on longitudinal sperm recovery after hematopoietic stem cell transplantation. Here, the Late Effects Working Party of the European Group for Blood and Marrow Transplantation reports data of sperm analysis from 224 males who underwent hematopoietic stem cell transplantation. Median time between transplantation and sperm analysis was 63 months (8–275 months). At last sperm analysis, presence of any degree of spermatozoa was reported in 70 (31%) and complete azoospermia in 154 (69%) patients. In multivariate analysis, being conditioned with total body irradiation (RR 7.1; 95% CI: 3.4–14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09–5.2) were significantly associated with higher risk for azoospermia. In patients not conditioned with total body irradiation, ongoing chronic graft-versus-host disease is the main adverse factor for sperm recovery (RR of 3.11; 95% CI: 1.02–9.47; P=0.045). Already established risk factors, such as total body irradiation and age older than 25 years at hematopoietic stem cell transplantation, were seen to be the most relevant adverse risk factor for sperm production after hematopoietic stem cell transplantation. Furthermore, for the first time, ongoing graft-versus-host disease has been shown to be the most relevant adverse factor for sperm recovery, particularly in patients conditioned without total body irradiation. We also introduce a useful scoring system to predict the probability of male long-term survivors’ azoospermia. PMID:22929982

  19. Persistent CMV infection after allogeneic hematopoietic stem cell transplantation in a CMV-seronegative donor-to-positive recipient constellation: Development of multidrug resistance in the absence of anti-viral cellular immunity.

    PubMed

    Herling, Marco; Schröder, L; Awerkiew, Sabine; Chakupurakal, Geothy; Holtick, Udo; Kaiser, Rolf; Pfister, Herbert; Scheid, Christof; Di Cristanziano, Veronica

    2016-01-01

    We describe a case of persistent cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with discordant and high-risk (D-/R+) constellation of CMV serostatus. Despite the use of different and innovative antiviral strategies, viral replication could not be suppressed successfully promoting a protracted CMV colitis associated with severe gastrointestinal graft-versus-host disease (GI GVHD). We illustrate that the development of multidrug viral resistance, the failure to mount a CMV-specific cellular immune response, as confirmed by QuantiFERON(®)-CMV (Qiagen) assay, and the refractory GVHD requiring prolonged immunosuppression were the main factors contributing to persistent viral replication and the fulminant unfavorable course.

  20. Types of Stem Cells

    MedlinePlus

    ... PDF) Download an introduction to stem cells and stem cell research. Stem Cell Glossary Stem cell terms to know. ... stem cells blog from the International Society for Stem Cell Research. Learn About Stem Cells From Lab to You ...

  1. Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT.

    PubMed

    Cahu, X; Labopin, M; Giebel, S; Aljurf, M; Kyrcz-Krzemien, S; Socié, G; Eder, M; Bonifazi, F; Bunjes, D; Vigouroux, S; Michallet, M; Stelljes, M; Zuckerman, T; Finke, J; Passweg, J; Yakoub-Agha, I; Niederwieser, D; Sucak, G; Sengeløv, H; Polge, E; Nagler, A; Esteve, J; Mohty, M

    2016-03-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan-cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged ⩾35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens. PMID:26618548

  2. The Effect of GVHD on Long-term Outcomes after Peripheral Blood Allogeneic Stem Cell Transplantation from an HLA-identical Sibling in Adult Acute Lymphocytic Leukemia: A Landmark Analysis Approach in Competing Risks.

    PubMed

    Jalali, Arash; Alimoghaddam, Kamran; Mahmoudi, Mahmood; Mohammad, Kazem; Mousavi, Seied Asadollah; Bahar, Babak; Vaezi, Mohammad; Zeraati, Hojjat; Jahani, Mohammad; Ghavamzadeh, Ardeshir

    2014-01-01

    Allogeneic Hematopoietic stem cell transplantation (HSCT) is the most effective therapy to prevent relapse in acute lymphocytic leukemia (ALL). This benefit is affected by non-relapse mortality (NRM) due to complications such as graft versus host disease (GVHD). A new approach in analyzing time-dependent covariates in competing risks is landmark analysis. So, the aim of this study is to evaluate the effect of acute and chronic GVHD on long-term outcomes, relapse and NRM, after allogeneic HSCT in adult ALL using landmark analysis. This study was conducted on 252 ALL patients who were allogeneic transplanted from an HLA-identical sibling with peripheral blood (PB) as the source of stem cell from 2004 to 2012 and were followed-up until 2013. In the first 100 days after transplant, a landmark analysis on days +10, +11, +12, +17, +24, and +31 was applied to assess the effect of acute GVHD on early relapse and NRM. Similarly, for patients alive and event-free at day +100 after transplant, a landmark analysis at time points day +101, months +4, +5, +6, +9, and +12 was applied to evaluate the effect of chronic GVHD on late relapse and NRM. Five-year LFS and OS were 35.0% (95% CI: 29.1, 42.2%) and 37.5% (95% CI: 31.3, 45.0%), respectively. Five-year cumulative incidence of relapse was 44.5% (95% CI: 37.9, 51.0%) while this was 20.4% (95% CI: 15.4, 26.0%) for NRM. The landmark analysis in the first 100 days after transplant showed that the grade III/IV of aGVHD has a lower risk of relapse but higher risk of NRM after adjustment for the EBMT risk score. For patients alive at day +100, cGVHD had no significant effect on relapse. Limited cGVHD had lower risk of NRM and after 6 month post-transplant the risk of NRM decreased and there were not important difference between the groups of cGVHD. Using advanced models enables us to estimate the effects more precisely and ultimately make inference more accurately.

  3. Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting.

    PubMed

    Giménez, Estela; Blanco-Lobo, Pilar; Muñoz-Cobo, Beatriz; Solano, Carlos; Amat, Paula; Pérez-Romero, Pilar; Navarro, David

    2015-09-01

    The role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and that of antibodies neutralizing virus epithelial infection (AbNEI) in the control of CMV DNAemia were investigated in 39 CMV-seropositive allogeneic stem-cell transplant (Allo-SCT) recipients with (n = 24) or without (n = 15) CMV DNAemia. AbNEI levels were monitored prospectively by means of a neutralization assay employing retinal epithelial cells (ARPE-19) and the recombinant CMV strain BADrUL131-Y4. Quantification of CMV-specific polyfunctional CD8+ T-cells (expressing two or three of the following markers: IFN-γγ, TNF-α and CD107a) in whole blood was performed by flow cytometry for intracellular cytokine staining. We found no differences in the dynamic pattern of AbNEI in patients with or without subsequent CMV DNAemia. Baseline and peak AbNEI titres were not predictive of the dynamics of CMV replication within episodes. No correlation was found between CMV DNA loads and AbNEI levels during episodes of CMV DNAemia (ρ = 0.09; 95 % confidence interval - 0.52 to 0.64; P = 0.78). The detection of pp65/IE-1 CMV-specific polyfunctional CD8+ T-cells was associated with low-level virus replication within subsequent episodes of CMV DNAemia. Interestingly, the presence of AbNEI titres (inverse) >4.7 log2 was predictive of the occurrence of CMV DNAemia (sensitivity, 83 %; specificity, 80 %). Our findings provide an insight to the role of humoral and cellular immunity in the control of CMV infection in an Allo-SCT setting.

  4. Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

    ClinicalTrials.gov

    2016-05-11

    Stem Cell Transplantation; Bone Marrow Transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation,; Genetic Diseases; Thalassemia; Pediatrics; Diamond-Blackfan Anemia; Combined Immune Deficiency; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Lymphoproliferative Disease; Metabolic Diseases

  5. Allogeneic hematopoietic cell transplantation: the state of the art

    PubMed Central

    Gyurkocza, Boglarka; Rezvani, Andrew; Storb, Rainer F

    2010-01-01

    Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. The field has evolved substantially over the past decade, with advances in patient and donor selection, stem cell sources, supportive care, prevention of complications and reduced-toxicity preparative regimens. As a result, the indications for HCT and the pool of eligible patients have expanded significantly. In this article, we provide an overview of the major aspects of allogeneic HCT, and focus specifically on areas of active research and on novel approaches to challenges in the field. Specifically, we will discuss approaches to reduce the toxicity of the preparative regimen, with the goal of increasing the safety and applicability of HCT. The availability of suitable donors may be an obstacle to wider application of HCT. We review three major approaches to broadening the donor pool: the use of HLA-mismatched unrelated donors, umbilical cord blood and HLA-haploidentical family donors. Graft-versus-host disease remains a major cause of morbidity and mortality after HCT. We review recent advances in the understanding of this phenomenon, and novel prophylactic and therapeutic approaches that hold the promise of further improving the safety of the procedure. We conclude with a speculative outline of the next 5 years of research in the field of HCT. PMID:20871781

  6. Acute GVHD is a strong predictor of full donor CD3+ T cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation.

    PubMed

    El-Cheikh, Jean; Vazquez, Alberto; Crocchiolo, Roberto; Furst, Sabine; Calmels, Boris; Castagna, Luca; Lemarie, Claude; Granata, Angela; Ladaique, Patrick; Oudin, Claire; Faucher, Catherine; Chabannon, Christian; Blaise, Didier

    2012-12-01

    The monitoring of chimerism is a standard procedure to assess engraftment and achievement of full donor lymphoid cells after reduced intensity conditioning (RIC) stem cell transplantation (Allo-SCT). However, there is no consensus on when and how often to monitor post-transplant chimerism. We retrospectively analyzed our experience regarding the impact of acute graft versus host disease (GVHD) for the prediction of allograft chimerism. One-hundred-and-fifteen patients transplanted between 2001 and 2010 were identified. This group included 57 females and 58 males with a median age of 50 years (range: 26-68). Patients evaluated in this study were adult patients with hematologic malignancies, who received transplants from an HLA-matched sibling donor or matched unrelated donor (MUD) at allele level so-called 10/10, and received the RIC regimen including fludarabine/busulfan and anti-thymoglobulin (ATG). Mixed T-cell chimerism was defined as between 5 and 94% recipient cells, and full chimerism was defined as the presence of more than 95% donor T-cell chimerism (TCC). Full donor TCC was achieved in 93 patients (81%) at a median of 77 days (range: 30-120) post-transplant. The cumulative incidence of Grade 2-4 GVHD in our population was 25% (95% CI 17-34). The analysis of the population of patients with acute GVHD grade ≥2 showed that at day 120 after Allo-SCT they all had a total full donor TCC. On the other hand, 78 (68%) patients without acute GVHD grade ≥2 presented with mixed chimerism (p = 0.002) on day 120 post-transplant. Interestingly, patients who received ATG 5 mg/kg obtained a higher probability of complete chimerism compared with those receiving 2.5 mg/kg (p = 0.03). In conclusion, our study demonstrates that acute GVHD was predictive of full donor TCC after RIC Allo-SCT. Therefore, our data may challenge the concept of the frequent or close monitoring of donor chimerism in some patients with ongoing acute GVHD. However, chimerism testing could represent

  7. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: part III. Prevention and treatment of relapse after allogeneic transplantation.

    PubMed

    de Lima, Marcos; Porter, David L; Battiwalla, Minoo; Bishop, Michael R; Giralt, Sergio A; Hardy, Nancy M; Kröger, Nicolaus; Wayne, Alan S; Schmid, Christoph

    2014-01-01

    In the Second Annual National Cancer Institute's Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Prevention and Treatment of Relapse after Allogeneic Transplantation highlighted progress in developing new therapeutic approaches since the first relapse workshop. Recent insights that might provide a basis for the development of novel, practical clinical trials were emphasized, including utilization of newer agents, optimization of donor lymphocyte infusion (DLI), and investigation of novel cellular therapies. Dr. de Lima discussed pre-emptive and maintenance strategies to prevent relapse after transplantation, for example, recent promising results suggestive of enhanced graft-versus-tumor activity with hypomethylating agents. Dr. Schmid provided an overview of adjunctive strategies to improve cell therapy for relapse, including cytoreduction before DLI, combination of targeted agents with DLI, and considerations in use of second transplantations. Dr. Porter addressed strategies to enhance T cell function, including ex vivo activated T cells and T cell engineering, and immunomodulatory approaches to enhance T cell function in vivo, including exogenous cytokines and modulation of costimulatory pathways.

  8. Allogeneic peripheral blood hematopoietic stem cell transplantation: guidelines for red blood cell immuno-hematological assessment and transfusion practice.Société Française de Greffe de Moelle.

    PubMed

    Lapierre, V; Kuentz, M; Tiberghien, P

    2000-03-01

    Allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) is presently being evaluated in a French randomized study comparing peripheral blood vs bone marrow. Cases of potentially lethal acute hemolysis have recently been reported after allogeneic PBSCT in the presence of a 'minor' ABO incompatibility. Patients were frequently transfused with recipient-compatible and donor-incompatible RBC and usually did not receive methotrexate in addition to cyclosporin A for graft-versus-host disease (GVHD) prophylaxis. In order to homogenize immuno-hematological (IH) assessment and transfusion practices within our protocol, we made proposals to 25 allo-transplant French centers on the following aspects: pre-inclusion IH assessment, IH exclusion criteria, transfusion rules, post-transplant IH surveillance and treatment of hemolysis. Analysis of responses to our proposals led to the elaboration of guidelines which were approved and implemented by the French Bone Marrow Transplantation Society (SFGM). Pre-inclusion IH testing includes mandatory detection and titration of anti-RBC allo-Ab, as well as titration of anti-A and anti-B Ab. The presence in the donor of an anti-A (group A or AB recipients), anti-B (group B or AB recipients) Ab with a titer >1/32 or the presence of allo-Ab against Rh, Kell, Fya, Fyb, Jka, Jkb, Ss Ag present on recipient RBC is an exclusion criterion for the protocol. ABO and RhD compatibility of RBC blood products with both HSC donor and recipient is mandatory. A similar compatibility is also required for Rh (other than D) and Kell Ag. If not possible, compatibility of RBC blood products with the HSC donor is mandatory. Lastly, guidelines regarding post-transplantation IH follow-up as well as acute hemolysis treatment have been elaborated. The implementation of these guidelines should contribute to enhancing the quality of transfusion practice after PBSCT. Such an approach will be applied to other aspects of transfusion medicine in the

  9. Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

    PubMed Central

    Bonifazi, Francesca; Storci, Gianluca; Bandini, Giuseppe; Marasco, Elena; Dan, Elisa; Zani, Elena; Albani, Fiorenzo; Bertoni, Sara; Bontadini, Andrea; De Carolis, Sabrina; Sapienza, Maria Rosaria; Rizzi, Simonetta; Motta, Maria Rosa; Ferioli, Martina; Garagnani, Paolo; Cavo, Michele; Mantovani, Vilma; Bonafè, Massimiliano

    2014-01-01

    Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36±570.06 vs. 838.10±282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280±0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism. PMID:24056816

  10. Treatment of Oral Mucositis in Hematologic Patients Undergoing Autologous or Allogeneic Transplantation of Peripheral Blood Stem Cells: a Prospective, Randomized Study with a Mouthwash Containing Camelia Sinensis Leaf Extract

    PubMed Central

    Carulli, Giovanni; Rocco, Melania; Panichi, Alessia; Chios, Chiara Feira; Ciurli, Ester; Mannucci, Chiara; Sordi, Elisabetta; Caracciolo, Francesco; Papineschi, Federico; Benedetti, Edoardo; Petrini, Mario

    2013-01-01

    Oral mucositis is an important side effect of hematopoietic stem cell transplantation (HCST), mainly due to toxicity of conditioning regimens. It produces significant pain and morbidity. The present study reports a prospective, randomized, non-blinded study testing the efficacy of a new mouthwash, called Baxidil Onco® (Sanitas Farmaceutici Srl, Tortona, Italy) in 60 hematologic patients undergoing HCST (28 autologous, 32 allogeneic). Baxidil Onco®, used three times a day from Day -1 to Day +30, in addition to standard prophylactic schedules, was administered to 14 patients undergoing autologous and 14 patients undergoing allogeneic HCST. The remaining 32 patients (14 autologous and 18 HCST) were treated only with standard prophylactic schedules and served as control. In our study, the overall incidence of oral mucositis, measured according to the World Health Organization 0-4 scale, was 50% in the Baxidl Onco® group versus 82% in the control group (P=0.022). In addition, a significant reduction in scale 2-4 oral mucositis was observed in the Baxidil Onco® group (25% vs 56.2%; P=0.0029). The results obtained indicate that incidence, severity and duration of oral mucositis induced by conditioning regimens for HCST can be significantly reduced by oral rinsing with Baxidil Onco®, in addition to the standard prophylaxis scheme. Since Camelia Sinensin extract, which is used to produce green tea, is the main agent in this mouthwash, we hypothesize that the anti-oxidative properties of polyphenolic compounds of tea might exert protective effects on oral mucosa. PMID:23888242

  11. High-Dose Y-90-Ibritumomab Tiuxetan Added to Reduced-Intensity Allogeneic Stem Cell Transplant Regimen for Relapsed or Refractory Aggressive B-Cell Lymphoma

    ClinicalTrials.gov

    2016-07-08

    Post-Transplant Lymphoproliferative Disorder; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

  12. The Use of Splenectomy to Manage Platelet Transfusion Refractoriness due to Anti-Human Leukocyte Antibodies in Allogeneic Stem Cell Transplantation

    PubMed Central

    Mauro, Margherita; Camoglio, Francesco; Piccoli, Pierluigi; De Bortoli, Massimiliano; Balter, Rita; Pegoraro, Anna; Cesaro, Simone

    2016-01-01

    In patients undergoing hematopoietic stem cell transplantation (HSCT), refractoriness to platelet transfusion has been associated with graft failure, delayed engraftment, early mortality and decreased overall survival. Therapeutic strategies include plasma exchange, immunoglobulins, rituximab, and splenectomy. We describe here three patients with refractoriness to platelet transfusion due to anti-human leukocyte antibodies who were splenectomized before HSCT (two cases) and after HSCT (one case) due to the lack of efficacy of other therapies. Splenectomy was uneventful. All three patients achieved a full donor engraftment. We suggest that splenectomy is feasible and effective in HSCT patients to reduce the risk of graft failure or delayed engraftment. PMID:27114815

  13. Influence of Stem Cell Source on Outcomes of Allogeneic Reduced-Intensity Conditioning Therapy Transplants Using Haploidentical Related Donors.

    PubMed

    Bradstock, Kenneth; Bilmon, Ian; Kwan, John; Blyth, Emily; Micklethwaite, Kenneth; Huang, Gillian; Deren, Stephanie; Byth, Karen; Gottlieb, David

    2015-09-01

    We compared outcomes for 2 retrospective cohorts of patients undergoing reduced-intensity conditioning (RIC) therapy transplants using haploidentical related donors and post-transplant prophylaxis against graft-versus-host disease (GVHD) with high-dose cyclophosphamide, tacrolimus, and mycophenolate. The first cohort of 13 was transplanted with bone marrow (BM) as the stem cell source, whereas the second cohort of 23 used peripheral blood stem cells (PBSCs) mobilized with granulocyte colony-stimulating factor. The BM cohort received a single 60-mg/kg dose of cyclophosphamide on day +3, whereas the PBSC cohort received 2 doses on days +3 and +4. Patients in the first cohort were slightly older and had a higher proportion of acute myeloid leukemia, but there were no differences in the distribution of Disease Risk Index scores between the 2 groups. Patients in the PBSC group received double the number of CD34(+) cells in the stem cell graft. Times to neutrophil and platelet recovery were not different between the 2 groups. Three patients, all in the PBSC group, failed to engraft but recovered with autologous hemopoiesis and survived. The 6-month cumulative incidences of acute GVHD were 55.1% for BM and 48.5% for PBSCs (P = .651), whereas 24-month cumulative rates for chronic GHVD were 28.6% for BM and 32.3% for PBSCs (P = .685). Only 2 patients, both in the BM group, died of nonrelapse causes, both of second cancers. The 2-year cumulative incidences of relapse were 43.9% for BM and 23.5% for PBSCs (P = .286). Overall survival at 2 years was significantly better for PBSC patients (P = .028), at 83.4% versus 52.7% for BM. Relapse-free and event-free survival did not differ significantly between BM and PBSC groups. In this retrospective analysis, we conclude that the use of PBSCs for haploidentical RIC transplants is a feasible strategy, with equivalent rates of acute and chronic GVHD and risk of relapse and low nonrelapse mortality compared with BM.

  14. Effects of T cell depletion in radiation bone marrow chimeras. III. Characterization of allogeneic bone marrow cell populations that increase allogeneic chimerism independently of graft-vs-host disease in mixed marrow recipients

    SciTech Connect

    Sykes, M.; Chester, C.H.; Sundt, T.M.; Romick, M.L.; Hoyles, K.A.; Sachs, D.H. )

    1989-12-01

    The opposing problems of graft-vs-host disease vs failure of alloengraftment severely limit the success of allogeneic bone marrow transplantation as a therapeutic modality. We have recently used a murine bone marrow transplantation model involving reconstitution of lethally irradiated mice with mixtures of allogeneic and syngeneic marrow to demonstrate that an allogeneic bone marrow subpopulation, removed by T cell depletion with rabbit anti-mouse brain serum and complement (RAMB/C), is capable of increasing levels of allogeneic chimerism. This effect was observed in an F1 into parent genetic combination lacking the potential for graft-vs-host disease, and radiation protection studies suggested that it was not due to depletion of stem cells by RAMB/C. We have now attempted to characterize the cell population responsible for increasing allogeneic chimerism in this model. The results indicate that neither mature T cells nor NK cells are responsible for this activity. However, an assay involving mixed marrow reconstitution in an Ly-5 congenic strain combination was found to be more sensitive to small degrees of stem cell depletion than radiation protection assays using three-fold titrations of bone marrow cells. Using this assay, we were able to detect some degree of stem cell depletion by treatment with RAMB/C, but not with anti-T cell mAb. Nevertheless, if the effects of alloresistance observed in this model are considered, the degree of stem cell depletion detected by such mixing studies in insufficient to account for the effects of RAMB/C depletion on levels of allogeneic chimerism, suggesting that another cell population with this property remains to be identified.

  15. The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function.

    PubMed

    Kong, Y; Wang, Y-T; Hu, Y; Han, W; Chang, Y-J; Zhang, X-H; Jiang, Z-F; Huang, X-J

    2016-02-01

    Poor graft function (PGF), including early and late PGF, is a serious complication following allotransplant. We recently reported that bone marrow microenvironment abnormalities may occur in cases of late PGF. Whether these abnormalities occur in early PGF remains unknown. To answer this question, we performed a nested case-control study comparing cellular elements of the bone marrow microenvironment in 10 subjects with early PGF, 30 subjects with late PGF and 40 subjects without PGF. Bone marrow endosteal cells, perivascular cells and endothelial cells were analyzed by flow cytometry and by hematoxylin-eosin and immunohistochemical staining in situ. Subjects with early and late PGF had similar abnormalities in these cell types compared with transplant recipients without PGF. However, none of the aforementioned elements of the bone marrow microenvironment were significantly different between early and late PGF patients. Our data suggest that similar abnormalities in the bone marrow microenvironment may occur in early and late PGF post allotransplant. Cellular approaches, such as the administration of mesenchymal stem cells, promise to be beneficial therapeutic strategies in patients with early or late PGF.

  16. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review.

    PubMed

    Yanagisawa, Ryu; Nakazawa, Yozo; Sakashita, Kazuo; Saito, Shoji; Tanaka, Miyuki; Shiohara, Masaaki; Shimodaira, Shigetaka; Koike, Kenichi

    2016-01-01

    An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft-versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting. We will make further efforts to increase the efficacy. PMID:26586462

  17. Long-term outcomes of fludarabine, melphalan and antithymocyte globulin as reduced-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiency disorders: a prospective single center study.

    PubMed

    Hamidieh, A A; Behfar, M; Pourpak, Z; Faghihi-Kashani, S; Fazlollahi, M R; Hosseini, A S; Movahedi, M; Mozafari, M; Moin, M; Ghavamzadeh, A

    2016-02-01

    Reduced-intensity conditioning (RIC) has offered many primary immunodeficiency disorder (PID) patients who are ineligible for myeloablative regimens a chance of cure. However, the beneficial role of RIC was questioned following reports suggesting higher chance of rejection and lower symptom resolution rate in mixed chimerism settings. Forty-five children affected by PIDs with a median age of 21 months underwent allogeneic hematopoietic stem cell transplantation in our institute from 2007 to 2013. All patients received an identical RIC regimen. Forty-one patients had successful primary engraftment (91%). Of the successful engraftments, 80% (n=33) had stable full donor chimerism at last contact. Overall, eleven transplant-related mortalities were reported including five patients due to sepsis, three children due to grade IV acute GvHD, two due to chronic GvHD and one patient due to sepsis after primary graft failure. The median post-transplantation follow-up of deceased patients was 55 days. Five-year overall survival and disease-free survival was 75.6% and 68.89%, respectively. All surviving patients with successful engraftment became disease free, regardless of having full or mixed chimerism. Our study suggests that RIC regimen provides satisfactory rates of successful engraftment and full chimerism. Furthermore, patients with mixed chimerism were stable in long-term follow-up and this chimerism status offered the potential to resolve symptoms of immunodeficiency. PMID:26595073

  18. Optimal time-points for minimal residual disease monitoring change on the basis of the method used in patients with acute myeloid leukemia who underwent allogeneic stem cell transplantation: a comparison between multiparameter flow cytometry and Wilms' tumor 1 expression.

    PubMed

    Rossi, Giovanni; Carella, Angelo Michele; Minervini, Maria Marta; di Nardo, Francesco; Waure, Chiara de; Greco, Michele Mario; Merla, Emanuela; Cillis, Giovanni Pio de; Di Renzo, Nicola; Melpignano, Angela; Capalbo, Silvana; Palumbo, Gaetano; Pisapia, Giovanni; Cascavilla, Nicola

    2015-02-01

    Minimal residual disease (MRD) of 30 adult AML patients was monitored by multiparameter flow cytometry (MFC) and WT1 expression before and after allogeneic stem cell transplantation (allo-SCT). Diagnostic performance of pre-transplant MRD measured by MFC was higher than that obtained by WT1 expression. Comparable results were displayed at day +30 post-transplant, while better values by WT1 compared to MFC were found at day +90. Positive MRD by MFC predicted a shorter disease free survival (DFS) before and 1 month after transplant (p=0.006 and p=0.005), while only high WT1 levels at 1 month from the transplant significantly impacted on DFS (p=0.010). Our results support the idea that MRD monitoring by MFC should be suggested before and 30 days after the transplant, while WT1 expression should be preferred after this procedure. The assessment of MRD at day +30 from allo-SCT is recommended as post transplant check-point for the predictive role displayed, independently of the method used.

  19. CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)—Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

    PubMed Central

    Schmidt-Hieber, M.; Silling, G.; Schalk, E.; Heinz, W.; Panse, J.; Penack, O.; Christopeit, M.; Buchheidt, D.; Meyding-Lamadé, U.; Hähnel, S.; Wolf, H. H.; Ruhnke, M.; Schwartz, S.; Maschmeyer, G.

    2016-01-01

    Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases. PMID:27052648

  20. Successful Treatment of Multifocal Histiocytic Sarcoma Occurring after Renal Transplantation with Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone (CLAG-M) Followed by Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Tomlin, Julia; Orosco, Ryan K.; Boles, Sarah; Tipps, Ann; Wang, Huan-You; Husseman, Jacob; Wieduwilt, Matthew

    2015-01-01

    Histiocytic sarcoma (HS) is a rare, aggressive malignancy. Lesions previously called HS were typically non-Hodgkin lymphomas, not HS. As such, chemotherapy directed at lymphoid neoplasms was frequently successful, but it is unclear if these regimens are ideal for HS. We present a 33-year-old African gentleman who underwent sequential renal transplants for glomerulonephritis. He subsequently developed HS of the upper airway and multiple cutaneous sites. The patient received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by salvage ifosfamide, carboplatin, and etoposide (ICE) but had continuous progression of cutaneous involvement. Cladribine, high-dose cytarabine, G-CSF, and mitoxantrone (CLAG-M) yielded a partial response with near resolution of disease. Ultimately, the patient achieved a complete remission after myeloablative allogeneic hematopoietic stem cell transplant. HS occurring after solid organ transplant raises the possibility of HS as a potential posttransplant malignancy. The use of CLAG-M has not been reported in HS. In this case, histiocyte-directed chemotherapy with CLAG-M was superior to lymphoma-directed regimens. PMID:26167311

  1. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS).

    PubMed

    Kröger, N; Shimoni, A; Zabelina, T; Schieder, H; Panse, J; Ayuk, F; Wolschke, C; Renges, H; Dahlke, J; Atanackovic, D; Nagler, A; Zander, A

    2006-02-01

    We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44-70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II-IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P = 0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36-34%, respectively. No difference in survival was seen between unrelated and related SCT.

  2. Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults.

    PubMed

    Le Bourgeois, Amandine; Peterlin, Pierre; Guillaume, Thierry; Delaunay, Jacques; Duquesne, Alix; Le Gouill, Steven; Moreau, Philippe; Mohty, Mohamad; Campion, Loïc; Chevallier, Patrice

    2016-08-01

    This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (≥615/mm(3); hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (≥395/mm(3); HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony-stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure. PMID:27118570

  3. Minimal residual disease after allogeneic stem cell transplant: a comparison among multiparametric flow cytometry, Wilms tumor 1 expression and chimerism status (Complete chimerism versus Low Level Mixed Chimerism) in acute leukemia.

    PubMed

    Rossi, Giovanni; Carella, Angelo Michele; Minervini, Maria Marta; Savino, Lucia; Fontana, Andrea; Pellegrini, Fabio; Greco, Michele Mario; Merla, Emanuela; Quarta, Gianni; Loseto, Giacomo; Capalbo, Silvana; Palumbo, Gaetano; Cascavilla, Nicola

    2013-12-01

    Relapse represents the main cause of treatment failure after allogeneic stem cell transplant (allo-SCT). The detection of minimal residual disease (MRD) by multiparametric flow cytometry (MFC), chimerism, cytogenetics and molecular analysis may be critical to prevent relapse. Therefore, we assessed the overall agreement among chimerism (low level mixed chimerism [LL-MC] vs. complete chimerism [CC]), MFC and Wilms tumor 1 (WT1) mRNA to detect MRD and investigated the impact of MRD obtained from the three methods on patient outcome. Sixty-seven fresh bone marrow (BM) samples from 24 patients (17 acute myeloid leukemia [AML], seven acute lymphoblastic leukemia [ALL]) in complete remission (CR) after allo-SCT were investigated at different time points. A moderate agreement was found among the three techniques investigated. A higher concordance between positive results from MFC (75.0% vs. 32.7%, p = 0.010) and WT1 (58.3% vs. 29.1%, p = 0.090) was detected among LL-MC rather than CC samples. Relapse-free survival (RFS) and overall survival (OS) were found to be higher in MRD negative patients than in MRD positive patients analyzed with MFC and WT1. Our results discourage the use of low autologous signals as the only marker of MRD, and suggest the usefulness of MFC and WT1 real-time quantitative polymerase chain reaction (RQ-PCR) in stratifying patients with respect to risk of relapse.

  4. Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL).

    PubMed

    Kröger, N; Bornhäuser, M; Stelljes, M; Pichlmeier, U; Trenschel, R; Schmid, C; Arnold, R; Martin, H; Heinzelmann, M; Wolschke, C; Meyer, R G; Bethge, W; Kobbe, G; Ayuk, F; Gökbuget, N; Hölzer, D; Zander, A; Beelen, D

    2015-12-01

    TBI-based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with ALL. We investigated toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide and cyclophosphamide for ALL within a prospective study. Major inclusion criteria were CR and non-eligibility for TBI. Fifty patients with a median age of 46.5 years (range, 18-64) were included. Donors were HLA-identical sibling (n=8), matched (n=42) or mismatched (n=10) unrelated. The toxicity was moderate, resulting in a cumulative incidence of non-relapse mortality (NRM) at 1 year of 8% (90% confidence interval: 2-15%). Acute GvHD grade II-IV and grade III/IV was noted in 53% and 14%, respectively. Chronic GvHD at one year was seen in 41%. After a median follow-up of 24 months the cumulative incidence of relapse was 36% (90% confidence interval: 24-48) and 51% (90% confidence interval: 37-65) at 1 and 2 years, respectively. The estimated 2-year disease-free and overall survivals were 36 and 48%, respectively. Treosulfan, etoposide and cyclophosphamide followed by AHSC has a favorable toxicity profile with low NRM and therefore represents a potential alternative regimen for ALL in 1. CR (NCT00682305).

  5. A reappraisal of ICU and long-term outcome of allogeneic hematopoietic stem cell transplantation patients and reassessment of prognosis factors: results of a 5-year cohort study (2009-2013).

    PubMed

    Platon, L; Amigues, L; Ceballos, P; Fegueux, N; Daubin, D; Besnard, N; Larcher, R; Landreau, L; Agostini, C; Machado, S; Jonquet, O; Klouche, K

    2016-02-01

    Epidemiology and prognosis of complications related to allogeneic hematopoietic stem cell transplant (HSCT) recipients requiring admission to intensive care unit (ICU) have not been reassessed precisely in the past few years. We performed a retrospective single-center study on 318 consecutive HSCT patients (2009-2013), analyzing outcome and factors prognostic of ICU admission. Among these patients, 73 were admitted to the ICU. In all, 32 patients (40.3%) died in ICU, 46 at hospital discharge (63%) and 61 (83.6%) 1 year later. Survivors had a significantly lower sequential organ failure assessment (SOFA) score, serum lactate and bilirubin upon ICU admission. Catecholamine support, mechanical ventilation (MV) and/or renal replacement therapy during ICU stay, a delayed organ support and an active graft versus host disease (GvHD) significantly worsen the outcome. By multivariate analysis, the worsening of SOFA score from days 1 to 3, the need for MV and the occurrence of an active GvHD were predictive of mortality. In conclusion, the incidence of HSCT-related complications requiring an admission to an ICU was at 22%, with an ICU mortality rate of 44%, and 84% 1 year later. A degradation of SOFA score at day 3 of ICU, need of MV and occurrence of an active GvHD are main predictive factors of mortality.

  6. [A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hematopoietic stem cell transplantation in adults: a cross-reflection on our organizations].

    PubMed

    Bourget, Philippe; Falaschi, Ludivine; Suarez, Felipe; Galland, Valérie; Blot, Dominique; Trompette, Caroline; Sibon, David; Fontbrune, Flore Sicre de; Merlette, Christophe; Vidal, Fabrice; Corriol, Odile; Giraud, Bérénice; Broissand, Christine; Clement, Rozenn; Hermine, Olivier

    2012-06-01

    Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and secu