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Sample records for allogenic stem cells

  1. Allogeneic hematopoietic stem cell transplantation in Tunisia.

    PubMed

    Ben Othman, T; Torjemane, L; Abdelkefi, A; Lakhal, A; Ladeb, S; Ben Hamed, L; Slama, H; Ben Abdeladhim, A

    2008-08-01

    In 1998, the Tunisian team of the 'Centre National de Greffe de Moelle Osseuse' initiated allogeneic hematopoietic SCT (AHSCT) in Tunisia. As of June 2007, information was collected about 299 patients with a first AHSCT and 12 additional retransplants. The median age was 19 years (range 2-49 years). The main indications were aplastic anemia (n=106, 36%), leukemia and nonmalignant disorders (n=153, 51%), Fanconi anemia (n=26, 9%) and other nonmalignant disorders (n=14, 4%). Preparative regimens depended on indication. All donors were HLA geno-identical. The stem cell sources were BM (87%) and PBSCs (13%). At the time of analysis, 200 patients (67%) were alive after a median follow-up of 42 months (range 3-112 months). The overall TRM rate was 17%. Outcome depended on indication. According to our results, allogeneic HSCT is potentially curative for hematological diseases, but it is a toxic approach for malignant disorders. PMID:18724288

  2. Regulatory T Cells in Allogeneic Stem Cell Transplantation

    PubMed Central

    Nagler, Arnon

    2013-01-01

    Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation. PMID:23737813

  3. 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. PMID:26172477

  4. Allogeneic hematopoietic stem cell transplantation in mycosis fungoides*

    PubMed Central

    Atalla, Angelo; Hallack Neto, Abrahão Elias; Siqueira, Denise Bittencourt; Toledo, Gabriela Cumani

    2013-01-01

    Mycosis Fungoides is typically an indolent disease in early stages. However, approximately 30% of patients have advanced staged disease at presentation and 20% will develop it at some time. These patients have a poorer prognosis with a median survival of 2-4 years. The only curative option for mycosis fungoides may be hematopoietic allogeneic stem cell transplantation. We report the case of a patient with mycosis fungoides in an advanced stage (IIB), refractory to treatment options. She underwent allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The patient remains in complete remission nineteen months after allo-HSCT. Allogeneic transplantation can alter the natural history of mycosis fungoides and should be considered in patients who have refractory disease or short-lived responses with standard therapies. PMID:24346924

  5. 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

  6. Allogenic benefit in stem cell therapy: cardiac repair and regeneration.

    PubMed

    Al-Daccak, R; Charron, D

    2015-09-01

    Stem cell (SC)-based therapies are a developing mean to repair, restore, maintain, or enhance organ functioning through life span. They are in particular a fast track to restore function in failing heart. Various types of SCs have been used in experimental and clinical studies showing the potential of these cells to revolutionize the treatment of heart diseases. Autologous cells have been privileged to overpass immunological barriers. The field has progressed tremendously and the hurdles, which have been largely overlooked in the excitement over the expected benefit the immunogenicity, have been revealed. Also, manufacturing of patient-specific clinical grade SC product, whether adult stem or reprogrammed induced pluripotent SCs, and the availability of these cells in sufficient amounts and status when needed is questionable. In contrast, adult SCs derived from healthy donors, thus allogeneic, have the advantage to be immediately available as an 'off-the-shelf' therapeutic product. The challenge is to overcome the immunological barriers to their transplantation. Recent research provided new insights into the mode of action and immune behavior of SCs in autologous as well as allogeneic settings. Lessons are learned and immune paradigms are changing: allogenicity, if balanced could be part of the dynamic and durable mechanisms that are critical to sustain cardiac regeneration and repair. We discuss the hurdles, lessons, and advances accomplished in the field through the progressive journey of cardiac-derived stem/progenitor cells toward allogeneic cardiac regenerative/reparative therapy. PMID:26206374

  7. 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

  8. 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

  9. 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

  10. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

    PubMed

    Halter, Joerg P; Michael, W; Schüpbach, M; Mandel, Hanna; Casali, Carlo; Orchard, Kim; Collin, Matthew; Valcarcel, David; Rovelli, Attilio; Filosto, Massimiliano; Dotti, Maria T; Marotta, Giuseppe; Pintos, Guillem; Barba, Pere; Accarino, Anna; Ferra, Christelle; Illa, Isabel; Beguin, Yves; Bakker, Jaap A; Boelens, Jaap J; de Coo, Irenaeus F M; Fay, Keith; Sue, Carolyn M; Nachbaur, David; Zoller, Heinz; Sobreira, Claudia; Pinto Simoes, Belinda; Hammans, Simon R; Savage, David; Martí, Ramon; Chinnery, Patrick F; Elhasid, Ronit; Gratwohl, Alois; Hirano, Michio

    2015-10-01

    Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation

  11. 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

  12. Immunological aspects of allogeneic and autologous mesenchymal stem cell therapies.

    PubMed

    Hoogduijn, M J; Roemeling-van Rhijn, M; Korevaar, S S; Engela, A U; Weimar, W; Baan, C C

    2011-12-01

    Mesenchymal stem cells (MSCs) have potential for therapeutic application as an immunomodulatory and regenerative agent. The immunogenicity and survival of MSCs after infusion are, however, not clear and evidence suggests that allogeneic but also autologous MSCs disappear rapidly after infusion. This may be associated with the susceptibility of MSCs to lysis by natural killer (NK) cells, possibly a result of culture-induced stress. In the present study we examined whether NK cell-mediated lysis of MSCs could be inhibited by immunosuppressive drugs. Human MSCs were isolated from adipose tissue and expanded in culture. Peripheral blood mononuclear cells were activated with interleukin (IL)-2 (200 U/ml) and IL-15 (10 ng/ml) for 7 days. CD3(-)CD16(+)CD56(+) NK cells were then isolated by fluorescence-activated cell sorting and added to europium-labeled MSCs for 4 hr in the presence or absence of immunosuppressive drugs. Lysis of MSCs was determined by spectrophotometric measurement of europium release. Nonactivated NK cells were not capable of lysing MSCs. Cytokine-activated NK cells showed upregulated levels of granzyme B and perforin and efficiently lysed allogeneic and autologous MSCs. Addition of tacrolimus, rapamycin or sotrastaurin to the lysis assay did not inhibit MSC killing. Furthermore, preincubation of activated NK cells with the immunosuppressive drugs for 24 hr before exposure to MSCs had no effect on MSC lysis. Last, addition of the immunosuppressants before and during the activation of NK cells, reduced NK cell numbers but did not affect their capacity to lyse MSCs. We conclude that the immunosuppressive drugs tacrolimus, rapamycin, and sotrastaurin are not capable of inhibiting the lysis of allogeneic and autologous MSCs by activated NK cells. Other approaches to controlling lysis of MSCs should be investigated, as controlling lysis may determine the efficacy of MSC therapy. PMID:21732766

  13. Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.

    PubMed

    Hirano, M; Martí, R; Casali, C; Tadesse, S; Uldrick, T; Fine, B; Escolar, D M; Valentino, M L; Nishino, I; Hesdorffer, C; Schwartz, J; Hawks, R G; Martone, D L; Cairo, M S; DiMauro, S; Stanzani, M; Garvin, J H; Savage, D G

    2006-10-24

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven. PMID:16971696

  14. 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

  15. 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

  16. 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

  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 STEM CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION

    PubMed Central

    Oran, Betul; Weisdorf, Daniel J.

    2016-01-01

    Purpose of review The optimal post-remission therapy of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. This review summarizes the recent developments in the clinical research and therapeutic applications defining the role of allogeneic hematopoietic stem cell transplantation (allo-HCT) in CR1. Recent findings Molecular markers in combinations with cytogenetics have improved the risk stratification and informed decision-making in patients with AML in CR1. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allo-HCT for a larger number of patients. Summary The progress in risk stratification and transplant technology dictate that early donor identification search should be initiated for all eligible AML patients in CR1. PMID:21912256

  19. ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Worel, Nina

    2016-01-01

    Summary Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for a variety of malignant and non-malignant hematological and congenital diseases. Due to the fact that the human leukocyte antigen system is inherited independently of the blood group system, approximately 40-50% of all HSCTs are performed across the ABO blood group barrier. The expected immune-hematological consequences after transplantation of an ABO-mismatched stem cell graft are immediate and delayed hemolytic complications due to presence of isohemagglutinins or passenger lymphocyte syndrome. The risks of these complications can partially be prevented by graft manipulation and appropriate transfusion support. Dependent on the kind of ABO mismatch, different effects on engraftment have been observed, e.g. delayed red blood cell recovery and pure red cell aplasia. Data on incidence of acute graft-versus-host disease (GVHD), non-relapse mortality, relapse, and overall survival are inconsistent as most studies include limited patient numbers, various graft sources, and different conditioning and GVHD prophylaxis regimens. This makes it difficult to detect a consistent effect of ABO-mismatched transplantation in the literature. However, knowledge of expectable complications and close monitoring of patients helps to detect problems early and to treat patients efficiently, thus reducing the number of fatal or life-threatening events caused by ABO-mismatched HSCT. PMID:27022317

  20. Role of allogeneic stem cell transplantation in mantle cell lymphoma.

    PubMed

    Cohen, Jonathon B; Burns, Linda J; Bachanova, Veronika

    2015-04-01

    Despite a wide spectrum of treatment options, mantle cell lymphoma (MCL) remains a challenging hematologic malignancy to manage. Advances in front-line therapy, including the monoclonal antibody rituximab and increasing use of cytarabine, have improved remission rates. Autologous hematopoietic cell transplantation (HCT) can effectively consolidate remission of MCL, leading to encouraging survival beyond 5 yr. However, nearly all patients with MCL will relapse and require salvage therapy. Novel agents such as ibrutinib, bortezomib, and lenalidomide have dramatically expanded the options for treating relapsed MCL. In this review, we summarize the clinical evidence supporting the use of allogeneic donor HCT in MCL and make recommendations on indications for its use. Data suggest that allogeneic donor HCT is the only curative therapy for patients with poor prognosis or aggressive MCL. Patient selection, timing, and optimal use remain a matter of scientific debate and given the rapidly changing therapeutic landscape of MCL, the outcomes of allogeneic HCT should be interpreted in the context of novel therapeutics. PMID:25154430

  1. Neutrophil function in children following allogeneic hematopoietic stem cell transplant.

    PubMed

    Kent, Michael W; Kelher, Marguerite R; Silliman, Christopher C; Quinones, Ralph

    2016-08-01

    HSCT is a lifesaving procedure for children with malignant and non-malignant conditions. The conditioning regimen renders the patient severely immunocompromised and recovery starts with neutrophil (PMN) engraftment. We hypothesize that children demonstrate minimal PMN dysfunction at engraftment and beyond, which is influenced by the stem cell source and the conditioning regimen. Peripheral blood was serially collected from children at 1 to 12 months following allogeneic HSCT. PMN superoxide (O2-) production, degranulation (elastase), CD11b surface expression, and phagocytosis were assessed. Twenty-five patients, mean age of 10.5 yr with 65% males, comprised the study and transplant types included: 14 unrelated cord blood stem cells (cords), seven matched related bone marrow donors, three matched unrelated bone marrow donors, and one peripheral blood progenitor cells. Engraftment occurred at 24 days. There were no significant differences between controls and patients in PMN O2- production, phagocytosis, CD11b surface expression, and total PMN elastase. Elastase release was significantly decreased <6 months vs. controls (p < 0.05) and showed normalization by six months for cords only. The conditioning regimen did not affect PMN function. PMN function returns with engraftment, save elastase release, which occurs later related to the graft source utilized, and its clinical significance is unknown. PMID:27114335

  2. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Maffini, Enrico; Giaccone, Luisa; Festuccia, Moreno; Brunello, Lucia; Busca, Alessandro; Bruno, Benedetto

    2016-06-01

    Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation. PMID:27043241

  3. [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. PMID:26160819

  4. Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma.

    PubMed

    Bhatt, Vijaya Raj

    2016-06-01

    Observational studies indicate a similar or higher probability of disease control, higher risk of non-relapse mortality (NRM), and similar overall survival (OS) with allogeneic stem cell transplantation (alloSCT), compared to autologous SCT, in relapsed or refractory non-Hodgkin lymphoma. Careful patient selection and utilization of reduced intensity conditioning (RIC) alloSCT may allow reduction in NRM. The optimal conditioning regimen and the roles of radioimmunotherapy, T cell depletion, and tandem SCT continue to be explored. Recent studies highlight comparable results with haploidentical SCT and cord blood SCT, thus providing alternate donor sources. Disease relapse and late effects continue to be major problems. Optimization of SCT techniques (e.g., improved graft-versus-host disease prophylaxis), post-transplant monitoring of minimal residual disease, and post-transplant maintenance, or pre-emptive therapy (e.g., with novel therapies) are emerging strategies to reduce the risk of relapse. Survivorship management using a multidisciplinary care approach, adoption of healthy lifestyle, and socioeconomic counseling are integral parts of a high-quality transplant program. PMID:26983957

  5. 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. PMID:25456787

  6. Sexual function 1-year after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Noerskov, K H; Schjødt, I; Syrjala, K L; Jarden, M

    2016-06-01

    Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is associated with short and long-term toxicities that can result in alterations in sexual functioning. The aims of this prospective evaluation were to determine: (1) associations between HSCT and increased sexual dysfunction 1 year after treatment; and (2) associations between sexual dysfunction, body image, anxiety and depression. This controlled prospective cohort study was conducted from October 2010 to November 2013. Patients completed assessments 2-3 weeks before HSCT (N=124) and 1 year after treatment (N=63). Assessment included descriptive data, Sexual Functioning Questionnaire, Body Image Scale and Hospital Anxiety and Depression Scale. The results showed a significant decline in overall sexual function in both men and women (P=<0.001, P=0.010, respectively), although men generally scored higher than women. Forty-seven percent of men and 60% of women reported at least one physical sexual problem 1 year after HSCT. Patients with chronic GVHD trended toward reporting lower levels of sexual function. Finally, women with chronic GVHD scored lower than those without chronic GVHD on the sexual function problem subscale (P=0.008). Sexual dysfunction remains a major problem for men and women 1 year after HSCT and requires routine evaluation and treatment after HSCT. PMID:26878660

  7. No evidence of plasticity in hair follicles of recipients after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Rovó, Alicia; Meyer-Monard, Sandrine; Heim, Dominik; Arber, Caroline; Passweg, Jakob R; Gratwohl, Alois; Tichelli, André

    2005-08-01

    Here we show in a prospective quantitative study of 115 patients after allogeneic hematopoietic stem cell transplantation that hair follicles remain exclusively of recipient type despite full whole blood donor-type chimerism. Our data indicate that unmanipulated hematopoietic donor stem cells do not contribute directly to reconstitution even in an organ at highest need for repair. PMID:16038783

  8. Allogeneic stem cell transplantation with peripheral blood stem cells mobilized by pegylated G-CSF.

    PubMed

    Hill, Geoffrey R; Morris, Edward S; Fuery, Madonna; Hutchins, Cheryl; Butler, Jason; Grigg, Andrew; Roberts, Andrew; Bradstock, Ken; Szer, Jeffrey; Kennedy, Glen; Morton, James; Durrant, Simon

    2006-06-01

    Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF. PMID:16737933

  9. 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

  10. 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. PMID:26465970

  11. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation.

    PubMed

    Chen, Y; Scieux, C; Garrait, V; Socié, G; Rocha, V; Molina, J M; Thouvenot, D; Morfin, F; Hocqueloux, L; Garderet, L; Espérou, H; Sélimi, F; Devergie, A; Leleu, G; Aymard, M; Morinet, F; Gluckman, E; Ribaud, P

    2000-10-01

    Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period. Recipients of unrelated stem cell transplants were at higher risk. All patients received foscarnet; 8 subsequently received cidofovir. Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients. In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients. No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response. Therefore, acyclovir- and/or foscarnet-resistant HSV-1 infections after allogeneic stem cell transplantation have become a concern; current strategies need to be reassessed and new strategies must be evaluated in this setting. PMID:11049772

  12. I-131-Metaiodobenzylguanidine therapy with allogeneic cord blood stem cell transplantation for recurrent neuroblastoma.

    PubMed

    Sato, Yuya; Kurosawa, Hidemitsu; Fukushima, Keitaro; Okuya, Mayuko; Hagisawa, Susumu; Sugita, Kenichi; Arisaka, Osamu; Inaki, Anri; Wakabayashi, Hiroshi; Nakamura, Ayane; Fukuoka, Makoto; Kayano, Daiki; Kinuya, Seigo

    2012-01-01

    Iodine-131-metaiodiobenzylguanidine (131I-MIBG) therapy combined with allogeneic cord blood stem cell transplantation (SCT) was used to treat a 4-year-old girl with recurrent neuroblastoma. The patient experienced relapse 2 years after receiving first-line therapies, which included chemotherapy, surgical resection, irradiation, and autologous peripheral SCT. Although 131I-MIBG treatment did not achieve complete remission, the size of the tumor was reduced after treatment. Based on our findings, we suggest that 131I-MIBG treatment with myeloablative allogeneic SCT should be considered as first-line therapy for high-risk neuroblastoma patients when possible. PMID:23067429

  13. 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

  14. DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation

    PubMed Central

    Dhakal, B.; D'Souza, A.; Pasquini, M.; Saber, W.; Fenske, T. S.; Moss, R. B.; Drobyski, W. R.; Hari, P.; Abidi, M. Z.

    2016-01-01

    Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure. PMID:26941799

  15. Autologous and allogeneic hematopoietic stem cell transplantation for Multiple Sclerosis: perspective on mechanisms of action.

    PubMed

    Van Wijmeersch, Bart; Sprangers, Ben; Dubois, Bénédicte; Waer, Mark; Billiau, An D

    2008-07-15

    Multiple Sclerosis (MS) is a frequent demyelinating immune-mediated disease of the central nervous system (CNS) that affects principally young adults and leads to severe physical and cognitive impairment. The current standard treatment makes use of the immune modulators beta-interferon, glatiramer acetate and natalizumab, or immunosuppressants such as mitoxantrone. However, these agents are only partially effective and in a number of patients fail to achieve satisfactory disease control. Autologous hematopoietic stem cell transplantation (HSCT) is being explored in the treatment of severe MS as a means of delivering high-dose immunosuppression followed by 'rescue' of the immuno-hematopoietic system with autologous HSC. The potential therapeutic benefit is based on the concept of so-called 'resetting' the immune system. The use of allogeneic HSCT as a possible therapeutic approach for severe MS is inspired by case reports of MS patients that underwent allogeneic HSCT for a concomitant hematological malignancy, and subsequently is supported by data from rodent models of MS. Allogeneic HSCT may offer specific therapeutic effects, such as the replacement of the autoreactive immune compartment by healthy allogeneic cells and the development of a graft-versus-autoimmunity (GVA) effect. Here, we review the currently available experimental and clinical evidence to support the role of autologous and allogeneic HSCT in MS. PMID:18541311

  16. 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

  17. 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. PMID:26662284

  18. 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

  19. Donor cell leukemia after allogeneic peripheral blood stem cell transplantation: a case report and literature review.

    PubMed

    Murata, Makoto; Ishikawa, Yuichi; Ohashi, Haruhiko; Terakura, Seitaro; Ozeki, Kazutaka; Kiyoi, Hitoshi; Naoe, Tomoki

    2008-07-01

    A 49-year-old male developed recurrent acute myeloid leukemia 27 months after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical brother. The immunophenotype of the blastic cell population was incompatible with that of the pre-transplant blast cells; a mutation in C/EBPA gene was found in the pre-transplant blast cells that was not present in the post-transplant blast cells, and short tandem repeat analysis of marrow cells, which included 71% blasts, showed complete donor chimera. Thus, this recipient developed donor cell leukemia (DCL). The donor was healthy when DCL developed in the recipient as well as before donation of the peripheral blood stem cells. Only five cases of DCL after PBSCT have been reported in the literature. As a mechanism for the development of DCL, a vigorous proliferative demand on the donor cells, which often correlates with a higher likelihood of replication error or mutation, has been proposed. Peripheral blood stem cells might have an advantage in that they are associated with a low incidence of DCL development because PBSCT recipients receive a higher total cell dose than recipients of bone marrow or cord blood cells. PMID:18470599

  20. The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients

    PubMed Central

    Klyuchnikov, Evgeny; Bacher, Ulrike; Kröger, Nicolaus; Kazantsev, Ilya; Zabelina, Tatjana; Ayuk, Francis; Zander, Axel Rolf

    2011-01-01

    Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15–20% of patients remain refractory to chemoradiotherapy, and 20–40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies. PMID:20981158

  1. Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016.

    PubMed

    Ullmann, Andrew J; Schmidt-Hieber, Martin; Bertz, Hartmut; Heinz, Werner J; Kiehl, Michael; Krüger, William; Mousset, Sabine; Neuburger, Stefan; Neumann, Silke; Penack, Olaf; Silling, Gerda; Vehreschild, Jörg Janne; Einsele, Hermann; Maschmeyer, Georg

    2016-09-01

    Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria. PMID:27339055

  2. 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

  3. Fungemia caused by Zygoascus hellenicus in an allogeneic stem cell transplant recipient.

    PubMed

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

    2004-07-01

    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

  4. 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

  5. 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

  6. Reticulated platelets as a marker of platelet recovery after allogeneic stem cell transplantation.

    PubMed

    Michur, H; Maślanka, K; Szczepiński, A; Mariańska, B

    2008-12-01

    Reticulated platelets (RP) are the youngest forms of platelets in blood and reflect the rate of bone marrow platelet production. In the present study, we used flow cytometric analysis to determine the percentage of RPs in patients undergoing allogeneic stem cell transplantation. We investigated 10 patients after transplantation from HLA identical siblings: five with acute myeloid leukemia (AML), four with chronic myeloid leukemia (CML), and one patient with myelodysplastic syndrome (MDS). Of the patients examined, four patients underwent allogeneic bone marrow transplantation and six patients underwent peripheral blood stem cell transplantation. It was observed that the initially reduced percentage of RPs (2.9 +/- 1.7%; mean +/- SD) was significantly higher (P = 0.0109) in all patients (13.6 +/- 6.4%) in the following 10-26 days. The RP percentage peak preceded the recovery of peripheral platelet count up to 45.6 x 10(9)/l on average by 3 days. We found no difference in RP% between the AML and CML patients but we did observe that in CML patients the RP percentage increased on average 7 days earlier than in AML patients. The elevated RP percentage reflects increased bone marrow regeneration and can be considered an additional marker of thrombopoietic recovery in the patients undergoing allogeneic stem cell transplantation. PMID:18983304

  7. Porcine Intervertebral Disc Repair Using Allogeneic Juvenile Articular Chondrocytes or Mesenchymal Stem Cells

    PubMed Central

    Acosta, Frank L.; Metz, Lionel; Adkisson, Huston Davis; Liu, Jane; Carruthers-Liebenberg, Ellen; Milliman, Curt; Maloney, Michael

    2011-01-01

    Tissue engineering strategies for intervertebral disc repair have focused on the use of autologous disc-derived chondrocytes. Difficulties with graft procurement, harvest site morbidity, and functionality, however, may limit the utility of this cell source. We used an in vivo porcine model to investigate allogeneic non-disc-derived chondrocytes and allogeneic mesenchymal stem cells (MSCs) for disc repair. After denucleation, lumbar discs were injected with either fibrin carrier alone, allogeneic juvenile chondrocytes (JCs), or allogeneic MSCs. Discs were harvested at 3, 6, and 12 months, and cell viability and functionality were assessed qualitatively and quantitatively. JC-treated discs demonstrated abundant cartilage formation at 3 months, and to a lesser extent at 6 and 12 months. For the carrier and MSC-treated groups, however, there was little evidence of proteoglycan matrix or residual notochordal/chondrocyte cells, but rather a type I/II collagen-enriched scar tissue. By contrast, JCs produced a type II collagen-rich matrix that was largely absent of type I collagen. Viable JCs were observed at all time points, whereas no evidence of viable MSCs was found. These data support the premise that committed chondrocytes are more appropriate for use in disc repair, as they are uniquely suited for survival in the ischemic disc microenvironment. PMID:21910592

  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. Treatment Options for Transformed Lymphoma: Incorporating Allogeneic Stem Cell Transplantation in a Multimodality Approach

    PubMed Central

    Reddy, Nishitha; Savani, Bipin N

    2011-01-01

    Transformed non-Hodgkin’s lymphoma (TL) arising from follicular lymphoma carries a poor prognosis and the median survival time after transformation is approximately 10-12 months. Standard chemotherapy and radioimmunotherapy have offered promising responses however; the duration of response does not appear to last long. Several studies evaluating the role of autologous stem cell transplantation (auto-SCT) as a salvage regimen have been reported and a subset of patients benefit from this modality of treatment. With an improvement in supportive care, outcome after allogeneic stem cell transplantation (allo-SCT) has been improved significantly over past decades, however very limited data are available in TL. In the era of emerging novel therapies, the actual timing, optimal conditioning regimens and long term impact of the type of stem cell transplantation (auto-SCT vs. allo-SCT) is unclear. This review addresses the approaches to the management of patients with TL. PMID:21621630

  11. Optimal graft source for allogeneic hematopoietic stem cell transplant: bone marrow or peripheral blood?

    PubMed

    Adhikari, Janak; Sharma, Priyadarshani; Bhatt, Vijaya Raj

    2016-08-01

    Peripheral blood (PB), compared with bone marrow graft, has higher stem cell content, leads to faster engraftment and is more convenient for collection. Consequently, the use of PB graft has significantly increased in recent years. Although the use of PB graft is acceptable or even preferred to bone marrow graft in matched related donor allogeneic transplant due to a possibility of improved survival, PB graft increases the risk of chronic graft-versus-host disease and associated long-term toxicities in the setting of matched unrelated donor allogeneic transplant. In haploidentical transplant, mitigation of graft-versus-host disease with the use of post-transplant cyclophosphamide is a hypothesis-generating possibility; however, available studies have significant limitations to draw any definite conclusion. PMID:27168462

  12. Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma

    PubMed Central

    Schmitz, Marian F.; Otten, Henny G.; Franssen, Laurens E.; van Dorp, Suzanne; Strooisma, Theo; Lokhorst, Henk M.; van de Donk, Niels W.C.J.

    2014-01-01

    In the course of multiple myeloma, patients may develop a M-protein band different from the original: secondary monoclonal gammopathy of undetermined significance. In this retrospective single center analysis, we describe the occurrence and clinical relevance of secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation (post-transplant monoclonal gammopathy of undetermined significance). A total of 138 patients who had undergone 139 allogeneic stem cell transplantations (39.6% in the upfront setting and 60.4% for relapsed multiple myeloma) were included in the study. Sixty-seven (48.2%) patients developed secondary monoclonal gammopathy of undetermined significance, after a median latency of 6.9 months. Secondary monoclonal gammopathy of undetermined significance occurred more often in patients who achieved at least very good partial response after allogeneic stem cell transplantation, compared to partial response or less (54.8% vs. 26.5%; P=0.005). The incidence was also higher in the upfront setting as compared to relapsed disease, or with a sibling donor compared to matched unrelated donor, but less often after T-cell depletion. Importantly, development of post-transplant monoclonal gammopathy of undetermined significance as a time-dependent variable independently predicted for superior progression-free and overall survival (median progression-free survival 37.5 vs. 6.3 months, P<0.001; median overall survival 115.3 vs. 31.0 months, P=0.004). Clinicians should be aware of the benign nature of this phenomenon, and secondary monoclonal gammopathy of undetermined significance should not be confused with relapse or progression of disease. (Trial registered with trialregister.nl; HOVON 108: NTR 2958.) PMID:25193963

  13. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    PubMed Central

    Basak, Grzegorz W.; Soverini, Simona; Martinelli, Giovanni; Mauro, Michael J.; Müller, Martin C.; Hochhaus, Andreas; Chuah, Charles; Dufva, Inge H.; Rege-Cambrin, Giovanna; Saglio, Giuseppe; Michallet, Mauricette; Labussière, Hélène; Morisset, Stéphane; Hayette, Sandrine; Etienne, Gabriel; Olavarria, Eduardo; Zhou, Wei; Peter, Senaka; Apperley, Jane F.; Cortes, Jorge

    2011-01-01

    T315I+ Philadelphia chromosome–positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABLT315I mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome–positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABLT315I mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors. PMID:21926354

  14. Allogeneic adipose-derived stem cells regenerate bone in a critical-sized ulna segmental defect.

    PubMed

    Wen, Congji; Yan, Hai; Fu, Shibo; Qian, Yunliang; Wang, Danru; Wang, Chen

    2016-07-01

    Adipose-derived stem cells (ASCs) with multilineage potential can be induced into osteoblasts, adipocytes and chondrocytes. ASCs as seed cell are widely used in the field of tissue engineering, but most studies either use autologous cells as the source or an immunodeficient animal as the host. In our present study, we explored the feasibility of applying allogeneic ASCs and demineralized bone matrix (DBM) scaffolds for repairing tubular bone defects without using immunosuppressive therapy. Allogeneic ASCs were expanded and seeded on DBM scaffolds and induced to differentiate along the osteogenic lineage. Eight Sprague-Dawley (SD) rats were used in this study and bilateral critical-sized defects (8 mm) of the ulna were created and divided into two groups: with ASC-DBM constructs or DBM alone. The systemic immune response and the extent of bone healing were evaluated post-operatively. Twenty-four weeks after implantation, digital radiography (DR) testing showed that new bones had formed in the experimental group. By contrast, no bone tissue formation was observed in the control group. This study demonstrated that allogeneic ASCs could promote bone regeneration and repair tubular bone defects combined with DBM by histologically typical bone without systemic immune response. PMID:25819682

  15. 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

  16. Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Lucarelli, Barbarella; Merli, Pietro; Bertaina, Valentina; Locatelli, Franco

    2016-03-01

    The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naïve T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft-versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T-cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes. PMID:26588325

  17. Steroid Pulse Therapy for Blood Cell Recovery in Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Murata, Yutaka; Kudo, Yoko; Kakihana, Kazuhiko; Abe, Kumiko; Kobayashi, Takeshi; Doki, Noriko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2016-01-01

    Objective Steroid pulse therapy is used to relieve pancytopenias in our hospital and is effective in some patients. However, it is unclear which patients will benefit from such therapy. Thus, we retrospectively analyzed the clinical features of patients undergoing allogeneic hematopoietic stem cell transplantation who received steroid pulse therapy to facilitate recovery in their blood cell counts. Methods Between 2004 and 2012, 24 patients underwent steroid pulse therapy and the medical records of 17 of these evaluable patients (11 men, 6 women) were retrospectively reviewed. Bone marrow smears were assessed to calculate the proportion of hemophagocytic macrophages just prior to receiving pulse therapy. Results Steroid pulse therapy was started at a median of 15 days after transplantation (range, 10-28 days). The median white blood cell count was 0.02×10(3)/μL (range, 0.01-0.4×10(3)/μL). Eight patients responded to pulse therapy and subsequent engraftment was achieved in all responders. None of the patients who underwent cord blood transplantation responded to the pulse therapy. Among the non-responders, only two patients achieved engraftment and four of nine non-responders died within one month. When evaluating the efficacy of steroid pulse therapy according to the ferritin level and proportion of hemophagocytic macrophages among patients undergoing bone marrow or peripheral blood stem cell transplantation, both values were higher in responders than in non-responders. Conclusion We speculate that responders have a hemophagocytic syndrome which is responsive to steroid pulse therapy. Thus, our results imply that the use of ferritin levels in combination with the proportion of hemophagocytic macrophages may be useful for the early detection of potential hemophagocytic syndrome after hematopoietic stem cell transplantation. PMID:26984072

  18. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients

    PubMed Central

    Yew, P Y; Alachkar, H; Yamaguchi, R; Kiyotani, K; Fang, H; Yap, K L; Liu, H T; Wickrema, A; Artz, A; van Besien, K; Imoto, S; Miyano, S; Bishop, M R; Stock, W; Nakamura, Y

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID:26052909

  19. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients.

    PubMed

    Yew, P Y; Alachkar, H; Yamaguchi, R; Kiyotani, K; Fang, H; Yap, K L; Liu, H T; Wickrema, A; Artz, A; van Besien, K; Imoto, S; Miyano, S; Bishop, M R; Stock, W; Nakamura, Y

    2015-09-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID:26052909

  20. Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem cell transplantation: a clinical pilot study.

    PubMed

    Or, R; Ackerstein, A; Nagler, A; Kapelushnik, J; Naparstek, E; Samuel, S; Amar, A; Bruatbar, C; Slavin, S

    1998-03-01

    Allogeneic cell therapy (allo-CT) is emerging as an effective treatment for patients relapsing after allogeneic bone marrow transplantation (BMT), indicating that tumor cells resisting chemoradiotherapy may still respond to immunocompetent allogeneic lymphocytes. We investigated possible graft-versus-tumor (GVT) effects in six patients with metastatic breast cancer that would be comparable to the graft-versus-leukemia (GVL) phenomenon occurring after allogeneic BMT in hematologic malignancies. The patients were cytoreduced with high-dose chemotherapy and autologous stem cell transplantation (ASCT), and were treated ambulatory with allo-CT consisting of adoptive transfer of HLA-matched donor peripheral blood lymphocytes (PBL) activated in vivo with human recombinant interleukin-2 (rIL-2). If no graft-versus-host disease (GVHD) developed, allo-CT was augmented with infusion of donor PBL, preactivated in vitro with rIL-2. Treatment was well tolerated, with low therapy-related toxicity in all patients. Two patients developed signs and symptoms compatible with GVHD grade I-II, one of whom shows no evidence of disease at more than 34 months out. In the remaining patients, progression-free survival following allo-CT ranged between 7 and 13 months. Allogeneic cell-mediated, cytokine-activated immunotherapy might be utilized for induction of GVT in metastatic breast cancer. A search for techniques to boost chimerism without severe GVHD is indicated. PMID:9557210

  1. Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation.

    PubMed

    Modi, Dipenkumar; Jang, Hyejeong; Kim, Seongho; Deol, Abhinav; Ayash, Lois; Bhutani, Divaya; Lum, Lawrence G; Ratanatharathorn, Voravit; Manasa, Richard; Mellert, Kendra; Uberti, Joseph P

    2016-09-01

    Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. © 2016 Wiley Periodicals, Inc. PMID:27238902

  2. Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival.

    PubMed

    Gorak, Edward; Geller, Nancy; Srinivasan, Ramaprasad; Espinoza-Delgado, Igor; Donohue, Teresa; Barrett, A John; Suffredini, Anthony; Childs, Richard

    2005-07-01

    Engraftment syndrome (ES) encompasses a constellation of symptoms that occur during neutrophil recovery after both autologous and allogeneic hematopoietic stem cell transplantation (HCT). Although it is well characterized after conventional myeloablative procedures, limited data exist on this complication after nonmyeloablative allogeneic HCT. The clinical manifestations, incidence, and risk factors associated with ES were investigated in a consecutive series of patients undergoing cyclophosphamide/fludarabine-based nonmyeloablative allogeneic HCT from a related HLA-compatible donor. Fifteen (10%) of 149 patients (median age, 53 years; range, 27-66 years) developed ES; the onset of symptoms occurred at a median of 10 days (range, 3-14 days), and they consisted of fever (100%), cough (53%), diffuse pulmonary infiltrates (100%), rash (13%), and room air hypoxia (87%). ES was more likely to develop in patients who received empiric amphotericin formulations after transplant conditioning (Fisher exact test; P=.007). In a multivariate analysis, older patient age, female sex, and treatment with amphotericin were predictors for the development of ES. Intravenous methylprednisolone led to the rapid resolution of ES; however, transplant-related mortality was significantly higher (cumulative incidence, 49% versus 16%; P=.0005), and median survival was significantly shorter (168 versus 418 days; P=.005) in patients with ES compared with non-ES patients. In conclusion, ES occurs commonly after cyclophosphamide/fludarabine-based nonmyeloablative transplantation and responds rapidly to corticosteroid treatment, but it is associated with a higher risk of nonrelapse mortality and with shorter overall survival. PMID:15983554

  3. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era

    PubMed Central

    Ramadan, Safaa M.; Di Veroli, Ambra; Camboni, Agnese; Breccia, Massimo; Iori, Anna Paola; Aversa, Franco; Cupelli, Luca; Papayannidis, Cristina; Bacigalupo, Andrea; Arcese, William; Lo-Coco, Francesco

    2012-01-01

    The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed. PMID:22689684

  4. Acute Fibrinous and Organizing Pneumonia Associated With Allogenic Hematopoietic Stem Cell Transplant Successfully Treated With Corticosteroids

    PubMed Central

    Nguyen, Lam-Phuong; Ahdoot, Stella; Sriratanaviriyakul, Narin; Zhang, Yanhong; Stollenwerk, Nicholas; Schivo, Michael; Harper, Richart

    2016-01-01

    Acute fibrinous and organizing pneumonia (AFOP) is an extremely rare, relatively new, and distinct histological pattern of acute lung injury characterized predominately by the presence of intra-alveolar fibrin and associated organizing pneumonia. AFOP may be idiopathic or associated with a wide spectrum of clinical conditions. It has a variable clinical presentation from mild respiratory symptoms to that similar to the acute respiratory distress syndrome. Currently there is no consensus on treatment, and corticosteroids previously were of unclear benefit. To date, there are less than 40 cases of AFOP reported in the literature and only one has been linked to hematopoietic stem cell transplantation. Here we report the first case series of 2 patients who developed AFOP following allogenic stem cell transplant that were successfully treated with high-dose corticosteroids. PMID:27152316

  5. Early Lung Computed Tomography Scan after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Cornetto, Marie Alice; Chevret, Sylvie; Abbes, Sarah; de Margerie-Mellon, Constance; Hussenet, Claire; Sicre de Fontbrune, Flore; Tazi, Abdellatif; Ribaud, Patricia; Bergeron, Anne

    2016-08-01

    A lung computed tomography (CT) scan is essential for diagnosing lung diseases in hematopoietic stem cell transplantation (HSCT) recipients. As a result, lung CT scans are increasingly prescribed in the early phase after allogeneic HSCT, with no assessment of the added value for global patient management. Among 250 patients who underwent allogeneic HSCT in our center over a 2-year period, we evaluated 68 patients who had at least 1 lung CT scan within the first 30 days post-transplantation. The median interval between allogeneic HSCT and lung CT scan was 8.5 days. Patients who underwent an early lung CT scan were more immunocompromised and had a more severe course. Fever was the main indication for the CT scan (78%). The lung CT scan was abnormal in 52 patients, including 17 patients who had an abnormal pre-HSCT CT scan. A therapeutic change was noted in 37 patients (54%) within 24 hours after the lung CT scan. The main changes included the introduction of corticosteroids (n = 23; 62%), especially in patients with a normal CT scan (89%). In univariate models, we found that a normal pretransplantation CT scan (P = .002), the absence of either dyspnea (P = .029) or hypoxemia (P = .015), and a serum C-reactive protein level <10 mg/L (P = .004) were associated with a normal post-HSCT lung CT scan. We found that the association of these variables could predict the normality of early post-HSCT lung CT scans. Pretransplantation lung CT scans are useful for the interpretation of subsequent lung CT scans following allogeneic HSCT, which are frequently abnormal. Early post-HSCT lung CT scans are helpful in patient management, but prescriptions could be more targeted. PMID:27189110

  6. Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Hong, Y C; Liu, H M; Chen, P S; Chen, Y J; Lyou, J Y; Hu, H Y; Yi, M F; Lin, J S; Tzeng, C-H

    2007-11-01

    Blood, buccal swab and hair follicles are among the most commonly used sources for forensic science, parentage testing and personal identification. A total of 29 patients who have had a sustained engraftment from 15 months to 21.5 years after allogeneic hematopoietic stem cell transplantation (HSCT) without rejection, relapse or chronic GVHD involving oral mucosa were enrolled for a chimerism study. PCR-amplified short tandem repeat analyses were conducted per patient every 3 months for at least three consecutive times. The results for blood were all donor type except one who had a mixed chimerism, 14.5 years after receiving a transplant for lymphoma. As for buccal swab, mixed chimerism ranging from 10 to 96% donor origin was noted for 28 recipients except the one who had mixed chimerism of blood and retained total recipient type. In contrast, hair follicles were 100% recipient type for the entire group. It is concluded that the hair follicle is devoid of adult stem cell plasticity and may serve as a reliable source of recipient's origin when pre-transplant DNA fingerprinting or reference DNA is not available for people who have successfully received allogeneic HSCT while in need of a personal identification. PMID:17704789

  7. Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

    PubMed Central

    Lin, Guiting; Lue, Tom F.

    2012-01-01

    Mesenchymal stem cells (MSCs) are well known for their immunomodulatory capabilities. In particular, their immunosuppressive property is believed to permit their allogeneic or even xenogeneic transplantation into immunocompetent recipients without the use of immunosuppressants. Adipose-derived stem cell (ADSC), owing to its ease of isolation from an abundant tissue source, is a promising MSC for the treatment of a wide range of diseases. ADSC has been shown to lack major histocompatibility complex-II expression, and its immunosuppressive effects mediated by prostaglandin E2. Both preclinical and clinical studies have shown that allogeneic transplantation of ADSCs was able to control graft-versus-host disease. In regard to xenotransplantation a total of 27 preclinical studies have been published, with 20 of them performed with the investigators' intent. All 27 studies used ADSCs isolated from humans, possibly due to the wide availability of lipoaspirates. On the other hand, the recipients were mouse in 13 studies, rat in 11, rabbit in 2, and dog in 1. The targeted diseases varied greatly but all showed significant improvements after ADSC xenotransplantation. For clinical application in human medicine, ADSC xenotransplantation offers no obvious advantage over autotransplantation. But in veterinary medicine, xenotransplantation with porcine ADSC is a practical alternative to the costly and inconvenient autotransplantation. PMID:22621212

  8. 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

  9. Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation.

    PubMed

    Link, C S; Teipel, R; Heidenreich, F; Rücker-Braun, E; Schmiedgen, M; Reinhardt, J; Oelschlägel, U; von Bonin, M; Middeke, J M; Muetherig, A; Trautmann-Grill, K; Platzbecker, U; Bornhäuser, M; Schetelig, J

    2016-06-01

    Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT. PMID:26752141

  10. Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation.

    PubMed

    Sackett, S D; Brown, M E; Tremmel, D M; Ellis, T; Burlingham, W J; Odorico, J S

    2016-04-01

    Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives. PMID:26970668

  11. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    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

  12. 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

  13. Transmission of Clostridium difficile During Hospitalization for Allogeneic Stem Cell Transplant

    PubMed Central

    Kamboj, Mini; Sheahan, Anna; Sun, Janet; Taur, Ying; Robilotti, Elizabeth; Babady, Esther; Papanicolaou, Genovefa; Jakubowski, Ann; Pamer, Eric; Sepkowitz, Kent

    2016-01-01

    OBJECTIVE To determine the role of unit-based transmission that accounts for cases of early Clostridium difficile infection (CDI) during hospitalization for allogeneic stem cell transplant. SETTING Stem cell transplant unit at a tertiary care cancer center. METHODS Serially collected stool from patients admitted for transplant was screened for toxigenic C. difficile through the hospital stay and genotyping was performed by multilocus sequence typing. In addition, isolates retrieved from cases of CDI that occurred in other patients hospitalized on the same unit were similarly characterized. Transmission links were established by time-space clustering of cases and carriers of shared toxigenic C. difficile strains. RESULTS During the 27-month period, 1,099 samples from 264 patients were screened, 69 of which had evidence of toxigenic C. difficile; 52 patients developed CDI and 17 were nonsymptomatic carriers. For the 52 cases, 41 had evidence of toxigenic C. difficile on the first study sample obtained within a week of admission, among which 22 were positive within the first 48 hours. A total of 24 sequence types were isolated from this group; 1 patient had infection with the NAP1 strain. A total of 11 patients had microbiologic evidence of acquisition; donor source could be established in half of these cases. CONCLUSIONS Most cases of CDI after stem cell transplant represent delayed onset disease in nonsymptomatic carriers. Transmission on stem cell transplant unit was confirmed in 19% of early CDI cases in our cohort with a probable donor source established in half of the cases. PMID:26486102

  14. Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice.

    PubMed

    Verda, Larissa; Kim, Duck An; Ikehara, Susumu; Statkute, Laisvyde; Bronesky, Delphine; Petrenko, Yevgeniya; Oyama, Yu; He, Xiang; Link, Charles; Vahanian, Nicholas N; Burt, Richard K

    2008-02-01

    Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model. PMID:17975228

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:26088931

  16. 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

  17. Teratocarcinomas Arising from Allogeneic Induced Pluripotent Stem Cell-Derived Cardiac Tissue Constructs Provoked Host Immune Rejection in Mice

    PubMed Central

    Kawamura, Ai; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kashiyama, Noriyuki; Ito, Emiko; Watabe, Tadashi; Masuda, Shigeo; Toda, Koichi; Hatazawa, Jun; Morii, Eiichi; Sawa, Yoshiki

    2016-01-01

    Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including 18F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models. PMID:26763872

  18. Donor-derived DNA in hair follicles of recipients after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Jacewicz, R; Lewandowski, K; Rupa-Matysek, J; Jedrzejczyk, M; Brzezinski, P M; Dobosz, T; Jonkisz, A; Szram, S; Komarnicki, M; Berent, J

    2010-11-01

    The hair follicles of recipients of allogeneic hematopoietic SCT (HSCT) constitute the tissue with the greatest need for regeneration after high-dose chemotherapy. Previous studies have shown a lack of donor-derived DNA in the hair follicles of recipients. Therefore, we carried out a study to determine whether male donor-derived genetic material can be found in female recipients' hair follicles after HSCT. Fluorescent-based PCR with analyses of Y-chromosome STR (Y-STR) and RQ-PCR with the sex-determining region Y (SRY) were used independently to evaluate chimerism status. Our results proved the existence of donor-derived stem DNA in the recipients' hair follicle cells. This report undermines the validity of data indicating that hair follicle cells maintain 100% of recipient origin. PMID:20173789

  19. Rhodococcus equi pneumonia and sepsis in an allogeneic haematopoietic stem cell transplant recipient

    PubMed Central

    Shahani, Lokesh

    2014-01-01

    Rhodococcus equi is an aerobic facultative intracellular organism that is known to infect cells of the macrophage–monocyte lineage. It is a common veterinary pathogen; however, the incidence of this infection in humans has risen and it has been recognised as an emerging opportunistic pathogen among the immunocompromised patients. We present the case of a patient with chronic myeloid leukaemia who had received allogenic stem cell transplant and presented to the hospital with clinical picture of pneumonia. Her condition worsened on initial broad spectrum antimicrobials and 3 weeks into her hospitalisation, R. equi was isolated from her broncheoalveolar lavage and blood cultures. Based on the susceptibility, therapy was changed to four active antimicrobials; however, the patient failed to improve and eventually died. This case highlights the importance of considering the diagnosis of R. equi among immunosuppressed patients early in the right clinical setting due to the high virulence associated with this organism. PMID:24943142

  20. 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

  1. 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

  2. Adverse Late and Long-Term Treatment Effects in Adult Allogeneic Hematopoietic Stem Cell Transplant Survivors.

    PubMed

    Mosesso, Kara

    2015-11-01

    Hematopoietic stem cell transplantation (HSCT) has become the standard of care for many malignant and nonmalignant hematologic diseases that don't respond to traditional therapy. There are two types: autologous transplantation (auto-HSCT), in which an individual's stem cells are collected, stored, and infused back into that person; and allogeneic transplantation (allo-HSCT), in which healthy donor stem cells are infused into a recipient whose bone marrow has been damaged or destroyed. There have been numerous advancements in this field, leading to marked increases in the number of transplants performed annually. This article--the first of several on cancer survivorship--focuses on the care of adult allo-HSCT survivors because of the greater complexity of their posttransplant course. The author summarizes potential adverse late and long-term treatment-related effects, with special focus on the evaluation and management of several cardiovascular disease risk factors that can occur either independently or concurrently as part of the metabolic syndrome. These risk factors are potentially modifiable with appropriate nursing interventions and lifestyle modifications. PMID:26473441

  3. Distress Screening in Allogeneic Hematopoietic Stem Cell (HSCT) Caregivers and Patients

    PubMed Central

    Bevans, Margaret; Wehrlen, Leslie; Prachenko, Olena; Soeken, Karen; Zabora, James; Wallen, Gwenyth R.

    2011-01-01

    Family caregivers of allogeneic hematopoietic stem cell transplant (HSCT) patients are at risk for experiencing significant psychological distress yet screening caregivers has not been well studied. Objective This analysis explored the psychometric characteristics of the Distress Thermometer (DT) by examining its relationship, sensitivity and specificity relative to the Brief Symptom Inventory 18 (BSI-18) and the Multidimensional Fatigue Symptom Inventory (MFSI) in a sample of allogeneic HSCT caregivers and patients. Methods Longitudinal data were drawn from an ongoing intervention study for HSCT caregivers and patients. Data from one hundred and fifty-six English-speaking adults where patients (n=65) were receiving their first allogeneic HSCT with at least one adult caregiver (n=91) were eligible for this analysis. Study questionnaires were administered at baseline, initial discharge and 6 weeks following discharge. Results Construct validity was supported by significant relationships (p<0.001) between the DT and the BSI-18 GSI and the MFSI-Emotional subscales for caregivers and patients. The diagnostic utility of the DT for patients was good (AUC=.85±.05, p=.001), while for caregivers it was poor (AUC=.61±.08, p=.28). A DT cut point of 5 was supported for patients (sensitivity=1.0, specificity=.68), while for caregivers there was less confidence (sensitivity=.70, specificity=.52). Caregivers and patients reporting a higher number of problems had a greater level of distress (p<0.001). Conclusions These findings support the validity of the DT in screening for distress in HSCT caregivers and patients. Although the diagnostic utility of the DT for HSCT caregivers may be limited, understanding factors associated with distress can guide practice for this understudied population. PMID:21626610

  4. A Characterization of the Oral Microbiome in Allogeneic Stem Cell Transplant Patients

    PubMed Central

    Ames, Nancy J.; Sulima, Pawel; Ngo, Thoi; Barb, Jennifer; Munson, Peter J.; Paster, Bruce J.; Hart, Thomas C.

    2012-01-01

    Background The mouth is a complex biological structure inhabited by diverse bacterial communities. The purpose of this study is to describe the effects of allogeneic stem cell transplantation on the oral microbiota and to examine differences among those patients who acquired respiratory complications after transplantation. Methodology/Principal Findings All patients were consented at the National Institutes of Health, Clinical Center. Bacterial DNA was analyzed from patients' oral specimens using the Human Oral Microbe Identification Microarray. The specimens were collected from four oral sites in 45 allogeneic transplantation patients. Specimens were collected at baseline prior to transplantation, after transplantation at the nadir of the neutrophil count and after myeloid engraftment. If respiratory signs and symptoms developed, additional specimens were obtained. Patients were followed for 100 days post transplantation. Eleven patients' specimens were subjected to further statistical analysis. Many common bacterial genera, such as Streptococcus, Veillonella, Gemella, Granulicatella and Camplyobacter were identified as being present before and after transplantation. Five of 11 patients developed respiratory complications following transplantation and there was preliminary evidence that the oral microbiome changed in their oral specimens. Cluster analysis and principal component analysis revealed this change in the oral microbiota. Conclusions/Significance After allogeneic transplantation, the oral bacterial community's response to a new immune system was not apparent and many of the most common core oral taxa remained unaffected. However, the oral microbiome was affected in patients who developed respiratory signs and symptoms after transplantation. The association related to the change in the oral microbiota and respiratory complications after transplantation will be validated by future studies using high throughput molecular methods. PMID:23144704

  5. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again.

    PubMed

    Toubert, A; Glauzy, S; Douay, C; Clave, E

    2012-02-01

    Assessment of the host immune status is becoming a key issue in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to persistent immune defects. In allo-HSCT, T-cell differentiation of donor progenitors within the recipient thymus is required to generate naive recent T-cell emigrants (RTE). These cells account for a durable T-cell reconstitution, generating a diverse T-cell receptor (TCR) repertoire and robust response to infections. It is now possible to quantify the production of RTE by measuring thymic T-cell receptor excision circles or 'TREC' which are small circular DNA produced during the recombination of the genomic segments encoding the TCR alpha chain. Here we discuss the role of thymic function in allo-HSCT. The pre-transplant recipient thymic function correlates with clinical outcome in terms of survival and occurrence of severe infections. Post-transplant, TREC analysis showed that the thymus is a sensitive target to the allogeneic acute graft-versus-host disease (GvHD) reaction but is also prone to recovery in young adult patients. In all, thymus is a key player for the quality of immune reconstitution and clinical outcome after allo-HSCT. Thymic tissue is plastic and it is a future challenge to halt or reverse thymic GVHD therapeutically by acting at the level of T-cell progenitors generation, thymic homing and/or epithelial thymic tissue preservation. PMID:22220718

  6. Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome.

    PubMed

    Bacigalupo, A; Lamparelli, T; Gualandi, F; Occhini, D; Bregante, S; Raiola, A M; Ibatici, A; di Grazia, C; Dominietto, A; Piaggio, G; Podesta, M; Bruno, B; Lombardi, A; Frassoni, F; Viscoli, C; Sacchi, N; Van Lint, M T

    2007-03-01

    We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome. PMID:17277788

  7. Kaposi's sarcoma following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia.

    PubMed

    de Medeiros, B C; Rezuke, W N; Ricci, A; Tsongalis, G; Shen, P U; Bona, R D; Feingold, J M; Edwards, R L; Tutschka, P J; Bilgrami, S

    2000-01-01

    Unlike solid organ transplantation, Kaposi's sarcoma (KS) occurs rarely following hematopoietic stem cell transplantation (HSCT). In fact, only 5 cases of KS have been reported after allogeneic or autologous HSCT. The usual treatment combines a substantial decrease in, or elimination of, immunosuppressive therapy along with local measures such as surgical excision, cryotherapy or radiation therapy. A 46-year-old woman with chronic myelogenous leukemia who had received an allogeneic HSCT previously from an HLA-identical sibling, presented on day +814 with human herpes virus-8-associated KS involving her left lower extremity. She had been on continuous immunosuppressive therapy since her transplant because of chronic graft-versus-host disease. The intensity of immunosuppressive therapy was decreased once a diagnosis of KS had been established. However, the nodular lesions continued to progress in size and number. Therefore, a course of irradiation was administered to sites of bulk disease on her legs. Furthermore, thalidomide was initiated along with a topical retinoid, alitretinoin 0.1% gel applied twice daily to the nonirradiated lesions. This approach yielded a partial response in both irradiated and nonirradiated lesions over the course of the following 7 months. Both thalidomide and alitretinoin 0.1% gel appear to be beneficial in HSCT-associated KS and exhibit tolerable side effects. PMID:11154986

  8. Survival in a recent cohort of mechanically ventilated pediatric allogeneic hematopoietic stem cell transplantation recipients.

    PubMed

    van Gestel, Josephus P J; Bollen, Casper W; Bierings, Marc B; Boelens, Jaap Jan; Wulffraat, Nico M; van Vught, Adrianus J

    2008-12-01

    There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies. PMID:19041061

  9. 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

  10. 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

  11. Allogeneic Hematopoietic Stem-Cell Transplantation for Myelofibrosis: A Practical Review.

    PubMed

    Farhadfar, Nosha; Cerquozzi, Sonia; Patnaik, Mrinal; Tefferi, Ayalew

    2016-07-01

    Myelofibrosis is a myeloproliferative neoplasm with cardinal features of extramedullary hematopoiesis, hepatosplenomegaly, cytopenias, and constitutional symptoms that result in shortened survival and leukemic transformation. It is a disease predominantly of the elderly, and currently available therapies only offer symptom control without curative benefit or ability to alter disease progression. Allogeneic hematopoietic stem-cell transplant (HSCT) is the only potentially curative intervention; however, this is only feasible in younger and medically fit patients and selectively offered to those with high-risk disease. Despite ongoing advancements, HSCT is associated with substantial morbidity and mortality, and the determination of which patients with myelofibrosis are ideal candidates and the selection of the opportune moment to proceed with transplantation remains challenging. This review summarizes our current recommendations for the role of and indications for HSCT in myelofibrosis. PMID:27407157

  12. Adult allogeneic haematopoietic stem cell transplantation: a single centre experience in Malaysia.

    PubMed

    Gan, G G; Zakaria, Z; Sangkar, J V; Haris, A R; Bee, P C; Chin, E; Teh, A

    2008-10-01

    We analysed the outcome of 104 patients from a single institution who underwent allogeneic haematopoietic stem cell transplantation (AHSCT) from their HLA-identical siblings between 1993 and 2006. Sixty-nine percent of patients had peripheral blood stem cell (PBSC) as the stem cell source and the remaining had bone marrow (BM). The majority of patients are Chinese (60%) followed by Malays (24%) and Indians (14%). The median time to reach white cell counts of >1 x 10(9)/L and platelet counts of >30 x 10(9)/L was 13 and 15 days, respectively in patients who had PBSC transplantation compared with 16 and 25 days in patients who had BM transplantation, (p < 0.0001 and p < 0.001). Acute graft-versus-host disease (aGVHD) of grade II to IV was observed in 34% of patients and chronic graft-versus-host disease (cGVHD) in 38% of patients. Although not statistically significant, there was a higher incidence of overall aGVHD in Indian patients (73%) compared to Chinese and Malays (57% and 56% respectively). There was no significant difference in the incidence of aGVHD and cGVHD with the source of stem cells. Overall survival (OS) and disease free survival (DFS) was 50% and 60% at five years respectively. Multivariate analysis showed that patients transplanted in standard risk and those who had limited cGVHD had a significant better OS, (p = 0.05 and p = 0.05). Patients who had cGVHD and transplanted in standard risk had a better DFS, (p = 0.002 and p < 0.001). In summary, AHSCT in standard risk patients is associated with a better outcome than those transplanted in high risk and although not statistically significant, there is a higher incidence of aGVHD in Indian patients. PMID:19385485

  13. 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

  14. 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

  15. Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies.

    PubMed

    Petropoulos, D; Worth, L L; Mullen, C A; Madden, R; Mahajan, A; Choroszy, M; Ha, C S; Champlin, R C; Chan, K W

    2006-03-01

    We evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i.v. x 4 days and melphalan 140 mg/m2 i.v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities. Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission. The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation. PMID:16435013

  16. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Jenq, Robert R.; Perales, Miguel-Angel; Littmann, Eric R.; Morjaria, Sejal; Ling, Lilan; No, Daniel; Gobourne, Asia; Viale, Agnes; Dahi, Parastoo B.; Ponce, Doris M.; Barker, Juliet N.; Giralt, Sergio; van den Brink, Marcel; Pamer, Eric G.

    2014-01-01

    Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT. PMID:24939656

  17. 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

  18. CXCR4-Related Increase of Circulating Human Lymphoid Progenitors after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Glauzy, Salomé; André-Schmutz, Isabelle; Larghero, Jérôme; Ezine, Sophie; de Latour, Régis Peffault; Moins-Teisserenc, Hélène; Servais, Sophie; Robin, Marie; Socié, Gérard

    2014-01-01

    Immune recovery after profound lymphopenia is a major challenge in many clinical situations, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recovery depends, in a first step, on hematopoietic lymphoid progenitors production in the bone marrow (BM). In this study, we characterized CD34+Lin−CD10+ lymphoid progenitors in the peripheral blood of allo-HSCT patients. Our data demonstrate a strong recovery of this population 3 months after transplantation. This rebound was abolished in patients who developed acute graft-versus-host disease (aGVHD). A similar recovery profile was found for both CD24+ and CD24− progenitor subpopulations. CD34+lin−CD10+CD24− lymphoid progenitors sorted from allo-HSCT patients preserved their T cell potentiel according to in vitro T-cell differentiation assay and the expression profile of 22 genes involved in T-cell differentiation and homing. CD34+lin−CD10+CD24− cells from patients without aGVHD had reduced CXCR4 gene expression, consistent with an enhanced egress from the BM. CCR7 gene expression was reduced in patients after allo-HSCT, as were its ligands CCL21 and CCL19. This reduction was particularly marked in patients with aGVHD, suggesting a possible impact on thymic homing. Thus, the data presented here identify this population as an important early step in T cell reconstitution in humans and so, an important target when seeking to enhance immune reconstitution. PMID:24621606

  19. Durable Scar Size Reduction Due to Allogeneic Mesenchymal Stem Cell Therapy Regulates Whole‐Chamber Remodeling

    PubMed Central

    Williams, Adam R.; Suncion, Viky Y.; McCall, Frederic; Guerra, Danny; Mather, Jacques; Zambrano, Juan P.; Heldman, Alan W.; Hare, Joshua M.

    2013-01-01

    Background Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy. Methods and Results Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post‐MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3‐dimensional cardiac magnetic resonance imaging angiography–derived anatomy to accurately target infarct border zone injections. MSC‐treated animals had a 19.62±2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09±2.31% from 3 to 6 months postinjection (P<0.0001). MSC‐treated animals had unchanged end‐diastolic volume (EDV; P=0.08) and end‐systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC‐treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69±1.68% to 35.85±2.74% at 3 months post‐MSC injection and progressed to 39.02±2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow‐up (P=0.33). Conclusion Intramyocardial injection of allogeneic MSCs leads to a sustained and

  20. Risk Factors and Impact of Secondary Failure of Platelet Recovery After Allogeneic Stem Cell Transplantation.

    PubMed

    Akahoshi, Yu; Kanda, Junya; Gomyo, Ayumi; Hayakawa, Jin; Komiya, Yusuke; Harada, Naonori; Kameda, Kazuaki; Ugai, Tomotaka; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Terasako-Saito, Kiriko; Kimura, Shun-Ichi; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Kanda, Yoshinobu

    2016-09-01

    Secondary failure of platelet recovery (SFPR), a late decrease in the platelet count after primary platelet recovery that is not due to relapse or graft rejection, occasionally occurs after allogeneic hematopoietic stem cell transplantation (HSCT). The risk factors and impact of SFPR on transplantation outcomes are not well known in the clinical setting. Therefore, we retrospectively evaluated 184 adult patients who underwent their first allogeneic HSCT and achieved primary platelet recovery. The cumulative incidence of SFPR, defined as a decrease in the platelet count to below 20,000/µL for more than 7 days, was 12.2% at 3 years, with a median onset of 81 days (range, 39 to 729) after HSCT. Among patients who developed SFPR (n = 23), 19 (82.6%) showed recovery to a sustained platelet count of more than 20,000/µL without transfusion support, and the median duration of SFPR was 23 days (range, 7 to 1048 days). A multivariate analysis showed that in vivo T cell depletion (hazard ratio [HR], 6.92; 95% confidence interval [CI], 2.31 to 20.7; P < .001), grades II to IV acute graft-versus-host disease (HR, 3.99; 95% CI, 1.52 to 10.5; P = .005), and the use of ganciclovir or valganciclovir (HR, 2.86; 95% CI, 1.05 to 7.77; P = .039) were associated with an increased risk for SFPR. The occurrence of SFPR as a time-dependent covariate was significantly associated with inferior overall survival (HR, 2.29; 95% CI, 1.18 to 4.46; P = .015) in a multivariate analysis. These findings may help to improve the management and treatment strategy for SFPR. PMID:27288954

  1. Bilateral Maxillary, Sphenoid Sinuses and Lumbosacral Spinal Cord Extramedullary Relapse of CML Following Allogeneic Stem Cell Transplant

    PubMed Central

    Hosseini, Soudabeh; Ansari, Shahla; Vosough, Parvaneh; Bahoush, Gholamreza; Hamidieh, Amir Ali; Chahardouli, Bahram; Shamsizadeh, Morteza; Mehrazma, Mitra; Dorgalaleh, Akbar

    2016-01-01

    Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. PMID:27252811

  2. Bilateral Maxillary, Sphenoid Sinuses and Lumbosacral Spinal Cord Extramedullary Relapse of CML Following Allogeneic Stem Cell Transplant.

    PubMed

    Hosseini, Soudabeh; Ansari, Shahla; Vosough, Parvaneh; Bahoush, Gholamreza; Hamidieh, Amir Ali; Chahardouli, Bahram; Shamsizadeh, Morteza; Mehrazma, Mitra; Dorgalaleh, Akbar

    2016-04-01

    Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. PMID:27252811

  3. Differential Gene Expression in Adipose Stem Cells Cultured in Allogeneic Human Serum Versus Fetal Bovine Serum

    PubMed Central

    Aho, Kaisa-Leena; Kuokkanen, Hannu; Räty, Sari; Huhtala, Heini; Lemponen, Riina; Yli-Harja, Olli; Suuronen, Riitta; Miettinen, Susanna

    2010-01-01

    In preclinical studies, human adipose stem cells (ASCs) have been shown to have therapeutic applicability, but standard expansion methods for clinical applications remain yet to be established. ASCs are typically expanded in the medium containing fetal bovine serum (FBS). However, sera and other animal-derived culture reagents stage safety issues in clinical therapy, including possible infections and severe immune reactions. By expanding ASCs in the medium containing human serum (HS), the problem can be eliminated. To define how allogeneic HS (alloHS) performs in ASC expansion compared to FBS, a comparative in vitro study in both serum supplements was performed. The choice of serum had a significant effect on ASCs. First, to reach cell proliferation levels comparable with 10% FBS, at least 15% alloHS was required. Second, while genes of the cell cycle pathway were overexpressed in alloHS, genes of the bone morphogenetic protein receptor–mediated signaling on the transforming growth factor beta signaling pathway regulating, for example, osteoblast differentiation, were overexpressed in FBS. The result was further supported by differentiation analysis, where early osteogenic differentiation was significantly enhanced in FBS. The data presented here underscore the importance of thorough investigation of ASCs for utilization in cell therapies. This study is a step forward in the understanding of these potential cells. PMID:20184435

  4. Outcomes of Autologous or Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma

    PubMed Central

    Reddy, Nishitha M.; Oluwole, Olalekan; Greer, John P.; Engelhardt, Brian G.; Jagasia, Madan H.; Savani, Bipin N.

    2016-01-01

    Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving auto (n=198) or allo-SCT (n=72) for NHL between year 2000 and 2010. Five-year overall survival for B-cell and T-cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T-cell lymphoma, respectively) (p=NS). In multivariate analysis, number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto and allo-SCT). We conclude that based on patient selection and disease related factors, the type of transplantation offered to patients can achieve long term survival highlighting the importance of further improvement in disease control and reducing procedure related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy. PMID:24096123

  5. 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

  6. MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation.

    PubMed

    Tomuleasa, Ciprian; Fuji, Shigeo; Cucuianu, Andrei; Kapp, Markus; Pileczki, Valentina; Petrushev, Bobe; Selicean, Sonia; Tanase, Alina; Dima, Delia; Berindan-Neagoe, Ioana; Irimie, Alexandru; Einsele, Hermann

    2015-07-01

    Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches. PMID:25900787

  7. Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

    PubMed Central

    Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD. PMID:27148267

  8. Intraarticular Injection of Allogenic Mesenchymal Stem Cells has a Protective Role for the Osteoarthritis

    PubMed Central

    Yang, Xin; Zhu, Tian-Yue; Wen, Li-Cheng; Cao, Yong-Ping; Liu, Chao; Cui, Yun-Peng; Meng, Zhi-Chao; Liu, Heng

    2015-01-01

    Background: Researchers initially proposed the substitution of apoptotic chondrocytes in the superficial cartilage by injecting mesenchymal stem cells (MSCs) intraarticularly. This effect was termed as bio-resurfacing. Little evidence supporting the treatment of osteoarthritis (OA) by the delivery of a MSC suspension exists. The aim of this study was to investigate the effects of injecting allogenic MSCs intraarticularly in a rat OA model and to evaluate the influence of immobility on the effects of this treatment. Methods: We established a rat knee OA model after 4 and 6 weeks and cultured primary bone marrow MSCs. A MSC suspension was injected into the articular space once per week for 3 weeks. A subgroup of knee joints was immobilized for 3 days after each injection, while the remaining joints were nonimmobilized. We used toluidine blue staining, Mankin scores, and TdT-mediated dUTP-biotin nick end labeling staining to evaluate the therapeutic effect of the injections. Comparisons between the therapy side and the control side of the knee joint were made using paired t-test, and comparisons between the immobilized and nonimmobilized subgroups were made using the unpaired t-test. A P value < 0.05 was considered significant. Results: The three investigative approaches revealed less degeneration on the therapy sides of the knee joints than the control sides in both the 4- and 6-week groups (P < 0.05), regardless of immobilization. No significant differences were observed between the immobilized and nonimmobilized subgroups (P > 0.05). Conclusions: Therapy involving the intraarticular injection of allogenic MSCs promoted cartilage repair in a rat arthritis model, and 3-day immobility after injection had little effect on this therapy. PMID:26365972

  9. 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. PMID:27246369

  10. Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole.

    PubMed

    Barajas, Megan R; McCullough, Kristen B; Merten, Julianna A; Dierkhising, Ross A; Bartoo, Gabriel T; Hashmi, Shahrukh K; Hogan, William J; Litzow, Mark R; Patnaik, Mrinal M; Wilson, John W; Wolf, Robert C; Wermers, Robert A

    2016-03-01

    Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase

  11. 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

  12. 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

  13. Alterations of circulating lymphoid committed progenitor cellular metabolism after allogeneic stem cell transplantation in humans.

    PubMed

    Glauzy, Salomé; Peffault de Latour, Régis; André-Schmutz, Isabelle; Lachuer, Joël; Servais, Sophie; Socié, Gérard; Clave, Emmanuel; Toubert, Antoine

    2016-09-01

    Lymphoid-committed CD34(+)lin(-)CD10(+)CD24(-) progenitors undergo a rebound at month 3 after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the absence of acute graft-versus-host disease (aGVHD). Here, we analyzed transcriptional programs of cell-sorted circulating lymphoid-committed progenitors and CD34(+)Lin(-)CD10(-) nonlymphoid progenitors in 11 allo-HSCT patients who had (n = 5) or had not (n = 6) developed grade 2 or 3 aGVHD and in 7 age-matched healthy donors. Major upregulated pathways include protein synthesis, energy production, cell cycle regulation, and cytoskeleton organization. Notably, genes from protein biogenesis, translation machinery, and cell cycle (CDK6) were overexpressed in progenitors from patients in the absence of aGVHD compared with healthy donors and patients affected by aGVHD. Expression of many genes from the mitochondrial oxidative phosphorylation metabolic pathway leading to ATP production were more specifically increased in lymphoid-committed progenitors in the absence of aGVHD. This was also the case for genes involved in cell mobilization such as those regulating Rho GTPase activity. In all, we found that circulating lymphoid-committed progenitors undergo profound changes in metabolism, favoring cell proliferation, energy production, and cell mobilization after allo-HSCT in humans. These mechanisms are abolished in the case of aGVHD or its treatment, indicating a persistent cell-intrinsic defect after exit from the bone marrow. PMID:27321893

  14. Extracoporeal photopheresis treatment of acute graft-versus-host disease following allogeneic haematopoietic stem cell transplantation

    PubMed Central

    Flinn, Aisling M.; Gennery, Andrew R.

    2016-01-01

    Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery. PMID:27408705

  15. Plasmodium falciparum causing hemophagocytic syndrome after allogeneic blood stem cell transplantation.

    PubMed

    Abdelkefi, Abderrahman; Ben Othman, Tarek; Torjman, Lamia; Ladeb, Saloua; Lakhal, Amel; Belhadj, Samir; Ayari, Sameh; Cherif, Nadra; Ben Achour, Oumaya; Chaker, Emna; Ben Abdeladhim, Abdeladhim

    2004-01-01

    We describe a case of Plasmodium falciparum infection in a 25-year-old male patient with a myelodysplastic syndrome, who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) in September 2003. Conditioning regimen consisted of total body irradiation (10 Gy) and cyclophosphamide 60 mg/kg for 2 days. A dose of 4 x 10(6) CD34+ cells/kg was transfused. Engraftment was well documented on day 17 post-transplantation. Spiking fevers occurred on days 19 and 21, associated with a pancytopenia, hepatosplenomegaly and neurological signs. P. falciparum parasites were found on the peripheral blood smear (parasitemia = 23%). Marrow aspiration showed P. falciparum parasites and proliferation of mature histiocytes with hemophagocytosis. Quinine 10 mg/kg i.v. three times a day for 10 consecutive days was given. The fever subsided within 3 days, and pancytopenia vanished in 14 days. Parasitemia cleared in 6 days. The patient left the unit on day 46 with no further complications. The screening of donors showed that infection was acquired from two blood units (from a single donor) given 5 days before transplantation. We report the first case of profound hemophagocytosis in immunosuppressed patient with malaria of high parasitemia after a bone marrow transplant. PMID:15448674

  16. Allogeneic peripheral blood stem cell transplantation for standard risk leukemia: experience of Ibni Sina Hospital.

    PubMed

    Arslan, O; Coşkun, H; Arat, M; Celebi, H; Ozcan, M; Gürman, G; Ustün, C; Demirer, T; Akan, H; Ilhan, O; Konuk, N; Beksaç, M; Uysal, A; Koç, H

    2000-06-01

    Fifty-three patients with standard risk leukemia who underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from their HLA-identical siblings were analyzed for engraftment, incidence and severity of GVHD, and relapse rate. Standard risk leukemia was defined as AML in first complete remission or CML in first chronic phase within the first year after diagnosis. The median age was 34.5 years (range 13-47). Stem cells were mobilized by using 10 microg/kg G-CSF subcutaneously for 5 days. A median of 5. 7 (2.1-21.4) x 106/kg CD34+ cells was collected over a median of 2 (range 1-5) apheresis procedures. Cyclosporin A (CsA) plus short-course MTX were used for GVHD prophylaxis. Recovery to granulocytes >0.5 x 109/l and platelets >20 x 109/l occurred at a median of day +13 (range 8-32) and +13 (range 8-51), respectively. Day +100 transplant-related mortality was 13.2% (7/53). Acute GVHD occurred in 20 of 49 (41%) evaluable patients and only six (12.3%) of them had severe disease (grade III-IV). Chronic GVHD occurred in 30 of 42 (71.4%) evaluable patients. Relapse rate at 2 years was 7. 5%. The median overall and leukemia-free survivals were 22 (4-44) and 20 (3-44) months, respectively. Estimated 4 year leukemia-free and overall survival rates were 60% and 62%, respectively. In conclusion, alloPBSCT in standard risk leukemia seems to be associated with a low relapse rate and no increased risk of acute GVHD, but there is a trend for higher incidence of cGVHD. Bone Marrow Transplantation (2000) 25, 1229-1232. PMID:10871726

  17. Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy.

    PubMed

    Filosto, Massimiliano; Scarpelli, Mauro; Tonin, Paola; Lucchini, Giovanna; Pavan, Fabio; Santus, Francesca; Parini, Rossella; Donati, Maria Alice; Cotelli, Maria Sofia; Vielmi, Valentina; Todeschini, Alice; Canonico, Francesco; Tomelleri, Giuliano; Padovani, Alessandro; Rovelli, Attilio

    2012-12-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us

  18. Feasibility of an exercise programme in elderly patients undergoing allogeneic stem cell transplantation - a pilot study.

    PubMed

    Schuler, M K; Hornemann, B; Pawandenat, C; Kramer, M; Hentschel, L; Beck, H; Kasten, P; Singer, S; Schaich, M; Ehninger, G; Platzbecker, U; Schetelig, J; Bornhäuser, M

    2016-09-01

    It has been demonstrated that physical exercise benefits younger patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). We designed a prospective pilot study investigating whether elderly patients (>60 years) would also be able to participate in such a programme. It consisted of physiotherapist-supervised alternating endurance and resistance workouts on 6 of 7 days a week. Sixteen consecutive patients undergoing allo-HSCT were enrolled into the study. The median age was 64.5 years. Twelve patients participated in the programme until the time of discharge (75%) from the transplant unit. Therefore, the predefined criteria regarding feasibility were met. The reason for drop out was transplantation associated mortality in all patients (n = 4). Adherence was very good with a median of 85% attended training sessions. No adverse events were recorded. The endurance capacity dropped by 7% and lower extremity strength improved by 2% over time. Quality of life decreased during the study period, with global health being significantly worse at the time of discharge. In conclusion, a combined and intensified strength and endurance exercise programme is feasible and safe in a population of elderly patients undergoing allo-HSCT. Further research should focus on exploring effect sizes of such an intervention by conducting randomised controlled trials. PMID:26526286

  19. Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Aoki, Jun; Numata, Ayumi; Yamamoto, Eri; Fujii, Eriko; Tanaka, Masatsugu; Kanamori, Heiwa

    2015-11-01

    Human herpesvirus-6 (HHV-6) is known to reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with development of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the clinical significance of HHV-6 reactivation after allo-HSCT remains unclear. Therefore, we conducted a retrospective analysis to elucidate the impact of HHV-6 reactivation on transplantation outcomes. Of 236 patients who underwent allo-HSCT, 138 (58.5%) developed HHV-6 reactivation and 98 (41.5%) did not. Univariate analysis indicated that at 3 years, patients with HHV-6 reactivation had significantly higher NRM (27.7% versus 13.7%, P = .003) and worse overall survival (42.1% versus 59.0%, P = .008) than those without reactivation. In multivariate analysis, HHV-6 reactivation was associated with higher incidence of acute GVHD (hazard ratio [HR], 1.87; P = .01), cytomegalovirus reactivation (HR, 2.24; P < .001), and NRM (HR, 2.73; P = .007). Subgroup analysis stratified according to conditioning intensity indicated that a significant impact of HHV-6 reactivation on acute GVHD was observed only in patients who received myeloablative conditioning (MAC). These results indicate that HHV-6 reactivation was associated with development of acute GVHD, cytomegalovirus reactivation, and NRM. Furthermore, adverse impact of HHV-6 reactivation on transplantation outcomes was prominent in the setting of MAC. PMID:26226409

  20. Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation.

    PubMed

    Weber, D; Oefner, P J; Dettmer, K; Hiergeist, A; Koestler, J; Gessner, A; Weber, M; Stämmler, F; Hahn, J; Wolff, D; Herr, W; Holler, E

    2016-08-01

    Intestinal dysbiosis has been associated with acute gastrointestinal GvHD and poor outcome following allogeneic stem cell transplantation (ASCT). To assess the effect of a switch in 2012 from ciprofloxacin/metronidazole to rifaximin for gut decontamination on intestinal microbiota composition and ASCT outcome, we retrospectively analyzed 394 patients receiving ASCT from September 2008 through June 2015. In 131 and 90 patients, respectively, urinary 3-indoxyl sulfate levels and intestinal enterococcal load were measured before conditioning and weekly within the first 28 days after ASCT. The use of rifaximin correlated with lower enterococcal positivity (6.9 vs 21.9%, P=0.05) and higher urinary 3-indoxyl sulfate concentrations (10.5 vs 4.6 μmoL/mmoL crea, P<0.001) after ASCT. Patients on rifaximin showed lower 1-year transplant-related mortality (P=0.04) and higher overall survival (P=0.008). Treatment of infectious complications with systemic antibiotics did not abrogate the beneficial effects of rifaximin on intestinal microbiota composition in the early course of ASCT and outcome. The data underscore the importance of maintaining a diverse population of symbiotic and mutualistic bacteria in the gut on ASCT outcome. PMID:26999466

  1. 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

  2. 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

  3. 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

  4. 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. PMID:27302479

  5. Pneumonia in allogeneic stem cell transplantation recipients: a multicenter prospective study.

    PubMed

    Aguilar-Guisado, Manuela; Jiménez-Jambrina, Margarita; Espigado, Ildefonso; Rovira, Montserrat; Martino, Rodrigo; Oriol, Albert; Borrell, Nuria; Ruiz, Isabel; Martín-Dávila, Pilar; de la Cámara, Rafael; Salavert, Miquel; de la Torre, Julián; Cisneros, José Miguel

    2011-01-01

    Pneumonia is a common cause of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) but updated and prospective information is partial. The aim of this nationwide prospective study is to determine the current epidemiology, etiology, and outcome of pneumonia in allo-HSCT recipients. From September-2003 to November-2005, 112 episodes in 427 consecutive allo-HSCT recipients were included (incidence 52.2 per 100 allo-HSCT/yr), and 72 of them (64.3%) were microbiologically defined pneumonia. Bacterial pneumonia (44.4%) was more frequent than fungal (29.2%) and viral pneumonia (19.4%). The most frequent microorganisms in each group were: Escherichia coli (n = 7, 8.9%), Streptococcus pneumoniae (n = 4, 5.0%), cytomegalovirus (n = 12, 15.4%), and Aspergillus spp. (n = 12, 15.4%). The development of pneumonia and chronic graft-versus-host disease (GVHD) was associated with increased mortality after allo-HSCT, and the probability of survival was significantly lower in patients that had at least one pneumonia episode (p < 0.01). Pneumonia development in the first 100 d after transplantation, fungal etiology, GVHD, acute respiratory failure, and septic shock were associated with increased mortality after pneumonia. Our results show that pneumonia remains a frequent infectious complication after allo-HSCT, contributing to significant mortality, and provide a large current experience with the incidence, etiology and outcome of pneumonia in these patients. PMID:22150886

  6. 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

  7. TLR5 stop codon polymorphism is associated with invasive aspergillosis after allogeneic stem cell transplantation.

    PubMed

    Grube, Matthias; Loeffler, Juergen; Mezger, Markus; Krüger, Bernd; Echtenacher, Bernd; Hoffmann, Petra; Edinger, Matthias; Einsele, Hermann; Andreesen, Reinhard; Holler, Ernst

    2013-11-01

    Single nucleotide polymorphisms (SNPs) have been associated with an increased incidence of invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT). We analyzed 41 patients with proven/probable IA after allo-SCT for an association of SNPs, within the TLR2, TLR4, TLR5, TLR9, and NOD2/CARD15 genes, with susceptibility to IA. The control group consisted of 130 patients who had allo-SCT but did not develop IA. While no association was found for donor SNPs and the recipients' risk of IA, analysis of recipient SNPs showed a significant association between the presence of recipient TLR5-Stop SNP (1174C> T) and the incidence of IA (P = 0.004). Multivariate analysis demonstrated that the recipient TLR5-Stop SNP appeared as an independent risk factor for IA after allo-SCT. Our study suggests that TLR5 is involved in host defense against Aspergillus fumigatus, and that the recipient TLR5-Stop SNP represents a risk factor for the development of IA after allo-SCT. PMID:23862689

  8. What do we need to know about allogeneic hematopoietic stem cell transplant survivors?

    PubMed

    Clark, C A; Savani, M; Mohty, M; Savani, B N

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for over 70 benign and malignant hematologic and immunological processes. Over the past several decades, significant technological and post-transplant supportive advances have been made, resulting in a decrease in early transplant mortality and continued growth in the population of allo-HSCT survivors. With the expansion in the number of long-term survivors, as well as of those considering a transplant, the focus of transplant medicine has been shifted significantly to include a more prominent role for the care of the 'long-term' survivor. These patients have survived the acute critical phase of transplantation and have potentially achieved remission from their primary disease, yet allo-HSCT patients do not return to pre-transplant health status. For survivors >2 years removed, the time of transplant all-cause mortality is four- to nine-fold higher than age-matched peers within the general population. These patients represent a distinct, high-risk population that must be monitored for long-term transplant complications, including chronic GvHD (cGvHD), multi-organ dysfunctions and secondary malignancies. This article will review in a non-exhaustive manner, the approach to long-term care of an allo-HSCT recipient. PMID:27064688

  9. [Allogeneic hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis type 1: a case report].

    PubMed

    Ou, Rui-Ming; Wang, Ling; Zheng, Li-Ling; Yao, Meng-Dong; Jiang, Wei-Tao; Zhou, Chang-Hua

    2006-06-01

    Mucopolysaccharidosis type I (MPS-I) is an inborn error of metabolism with progressive multisystem involvement. Hurler syndrome is the most severe form of MPS-I that causes progressive deterioration of the central nervous system with ensuing death. This study reported the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on Hurler syndrome in one case. The patient was a 25-month-old boy. He underwent allo-HSCT. The donor was his elder sister whose HLA-B locus was not matching. The reduced-intensity of BuCy conditioning regimen in allo-HSCT for this patient was as follows: busulfan 3.7 mg/kg daily at 9 to 6 days before transplantation, cyclophosphamide 42.8 mg/kg daily at 5 to 2 days before transplantation, and rabbit antithymocyte globulin 3.5 mg/kg daily at 1, 3, 5, and 7 days before transplantation. Human granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (CD34+ cells 12.8 x10(6)/kg) were infused and cyclosporine (CSA), short-course methotrexate, daclizumab and mycophenolate mofetil (MMF) were administered to prevent graft-versus-host disease (GVHD). Complete donor-type engraftment was confirmed by Short Tandem Repeat-Polymerase Chain Reaction (STR-PCR) on day 14 after transplantation. Neutrophil and platelet engraftment occurred on days 11 and 19 after transplantation respectively. Only grade I regimen-related toxicity of live and gastrointestinal tract occurred. GVHD and graft failure were not observed. After transplantation, the clinical symptoms and the neurocognitive function were greatly improved in this patient. It was concluded that allo-HSCT was effective for the treatment of MPS-I. The reduced-intensity conditioning regimen was helpful to decrease the regimen-related toxicity. Sufficient immunosuppressive therapy and adequate hematopoietic stem cells infusion may be beneficial to the donor cell engraftment and reducing the incidence of graft failure and GVHD. PMID:16787585

  10. 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.

  11. Acupoint injection of autologous stromal vascular fraction and allogeneic adipose-derived stem cells to treat hip dysplasia in dogs.

    PubMed

    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

  12. 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

  13. 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

  14. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning.

    PubMed

    Valcárcel, D; Martino, R; Caballero, D; Mateos, M V; Pérez-Simón, J A; Canals, C; Fernández, F; Bargay, J; Muñiz-Díaz, E; Gonzalez, M; San Miguel, J F; Sierra, J

    2003-03-01

    We have performed a prospective study to evaluate early chimerism and its kinetics after allogeneic peripheral blood stem cell transplantation among 68 patients who received a reduced-intensity conditioning (RIC) regimen with fludarabine plus melphalan (n=40) or busulphan (n=28). Chimerism was analyzed by polymerase chain reaction amplification of short tandem repeats in unfractionated (UF) and/or fractionated nucleated cells from bone marrow and peripheral blood (PB). All of the patients showed initial donor engraftment and no patient presented primary or secondary graft failure. In UF samples, the probability of achieving stable complete donor chimerism (CDC) in PB within the first 6 months was 70% on day +30, 85% on day +100 and 95% on day +180. CDC in granulocytes was observed in nearly all cases from day +30 onwards. CDC in T cells, however, differed among melphalan and busulphan recipients during the first 3 months (100 vs 0% on day +30 and 93 vs 20% on day +90, respectively). In multivariate analysis, the only significant variable associated with the achievement of early CDC was having received more than two lines of chemotherapy pretransplant (P<0.02). No correlation was found between the rate of achieving early CDC and the occurrence of acute graft-versus-host disease (GVHD) or disease progression post-transplant. In multivariate analysis, the only variable that influenced the incidence of disease progression post-transplant was the development of chronic extensive GVHD (P<0.05). In conclusion, a state of CDC is readily obtained within the first 6 months after our RIC protocols. Donor myeloid engraftment occurs rapidly in all cases, while early T-cell CDC is more common in more immunosuppressed hosts and, perhaps, in melphalan recipients. PMID:12634730

  15. 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

  16. Immunogenicity of decidual stromal cells in an epidermolysis bullosa patient and in allogeneic hematopoietic stem cell transplantation patients.

    PubMed

    Kaipe, Helen; Carlson, Lena-Maria; Erkers, Tom; Nava, Silvia; Molldén, Pia; Gustafsson, Britt; Qian, Hua; Li, Xiaoguang; Hashimoto, Takashi; Sadeghi, Behnam; Alheim, Mats; Ringdén, Olle

    2015-06-15

    Allogeneic mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but little is known about their immunogenicity. In this study, we monitored the therapeutic and immunogenic effects of decidual stromal cells (DSCs) from term placentas when used as a therapy for generalized severe junctional epidermolysis bullosa (JEB) (previously termed Herlitz JEB), a lethal condition caused by the lack of functional laminin-332. An 11-month-old JEB patient was treated with five infusions of allogeneic DSCs within a 3-month period. Amniotic membranes (AMs) were applied to severe wounds. After the treatment, wounds started to heal in the middle of the blisters, but the improvements were transient. After two infusions of DSCs, the JEB patient had developed multispecific anti-HLA class-I antibodies. No antibodies to laminin-332 were detected, but the patient had high levels of anti-bovine serum albumin antibodies, which could bind to DSCs. Peripheral blood mononuclear cells (PBMCs) from the patient had a higher proliferative response to DSCs than to third-party PBMCs, which contrasts with the pattern observed in healthy donors. Human DSCs and MSCs induced similar xenoreactivity in mice. Two of 16 allogeneic stem cell-transplanted patients, treated with DSCs for graft-versus-host disease or hemorrhagic cystitis, showed a positive flow cytometric crossmatch test. One patient had anti-HLA antibodies before DSC infusion, whereas the other had no anti-HLA antibodies at any time. AM and DSC infusions may have improved the healing process in the JEB patient, but DSCs appeared to induce anti-HLA antibodies. The risk of alloimmunization by DSCs seems to be low in immunocompromised patients. PMID:25658253

  17. Radiologically guided fine needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients.

    PubMed

    Jantunen, E; Piilonen, A; Volin, L; Ruutu, P; Parkkali, T; Koukila-Kähkölä, P; Ruutu, T

    2002-02-01

    Lung problems are common in allogeneic stem cell transplant (SCT) recipients. To evaluate the feasibility and diagnostic yield of radiologically guided fine needle lung biopsy (FNLB) in allogeneic SCT recipients with focal pulmonary lesions, a retrospective analysis was carried out. Between 1989 and 1998, radiologists performed a total of 30 FNLBs in 21 allogeneic SCT recipients, guided either by ultrasound (n = 17) or computed tomography (n = 13). The median time from SCT to the first FNLB was 131 days (20-343 days). Prophylactic platelet transfusions were given in 19 procedures (66%). The complications of FNLB included clinically insignificant pneumothorax in four procedures (13%) and self-limiting haemoptysis in one case (3%). The first FNLB was suggestive of invasive pulmonary aspergillosis (IPA) in five patients (24%). Additional clinically useful findings of FNLB included Pseudomonas (two patients) and Nocardia (one patient). The final diagnosis of pulmonary lesions was IPA in 14 patients, immunological lung problems in four patients and other in three patients. Radiologically guided FNLB is feasible in allogeneic SCT recipients and has a low complication rate. The diagnostic yield is high especially for IPA. PMID:11896433

  18. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).

    PubMed

    Koç, O N; Day, J; Nieder, M; Gerson, S L; Lazarus, H M; Krivit, W

    2002-08-01

    Patients with Hurler syndrome (mucopolysaccharidosis type-IH) and metachromatic leukodystrophy (MLD) develop significant skeletal and neurologic defects that limit their survival. Transplantation of allogeneic hematopoietic stem cells results in partial correction of the clinical manifestations. We postulated that some of these defects may be corrected by infusion of allogeneic, multipotential, bone marrow-derived mesenchymal stem cells (MSC). Patients with Hurler syndrome (n = 5) or MLD (n = 6) who previously underwent successful bone marrow transplantation from an HLA-identical sibling were infused with 2-10 x 10(6)/kg MSCs, isolated and expanded from a bone marrow aspirate of the original donor. There was no infusion-related toxicity. In most recipients culture-purified MSCs at 2 days, 30-60 days and 6-24 months after MSC infusion remained of host type. In two patients the bone marrow-derived MSCs contained 0.4 and 2% donor MSCs by FISH 60 days after MSC infusion. In four patients with MLD there were significant improvements in nerve conduction velocities after MSC infusion. The bone mineral density was either maintained or slightly improved in all patients. There was no clinically apparent change in patients' overall health, mental and physical development after MSC infusion. We conclude that donor allogeneic MSC infusion is safe and may be associated with reversal of disease pathophysiology in some tissues. The role of MSCs in the management of Hurler syndrome and MLD should be further evaluated. PMID:12203137

  19. 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

  20. Allogeneic peripheral blood stem cell transplantation in acute non-lymphoblastic leukemia.

    PubMed

    Arslan, O; Ustün, C; Arat, M; Celebi, H; Akan, H; Beksaç, M; Ilhan, O; Gürman, G; Ozcan, M; Konuk, N; Uysal, A; Koç, H

    1998-12-01

    Unmodified allogeneic peripheral blood stem cell transplantation (alloPBSCT) was performed in 20 consecutive acute non-lymphoblastic leukemia (ANLL) patients from their HLA-identical siblings. There were 11 males and 9 females. Median age was 34 years (range 17-43). Donors were primed with 2.5-15 micrograms/kg/day s.c. granulocyte-colony stimulating factor (G-CSF, Neupogen, Roche). Conditioning regimen was Bu (16 mg/kg) + Cy (120 mg/kg) in 19 patients and high dose Ara-C (3 gr/m2 twice daily for 3 days) for one patient who relapsed after bone marrow transplantation. Eighteen patients were in CR1. CsA + short-term MTX (n = 19) or CsA alone (n = 1) were used for graft versus host disease (GVHD) prophylaxis. The median number of apheresis procedures for each patient was 2 (2-4). A median of 6.5 (3.2-38.2) x 10(8)/kg MNC or 9.4 (2.2-12.4) x 10(6)/kg CD34+ cells were given. Median days to reach granulocyte of > 0.5 x 10(9)/l and platelet of > 50 x 10(9)/l were 12 (10-14) and 15 (11-35) respectively. Day 100 transplant-related mortality was 20 per cent (4/20). Grade 2 to 4 AGVHD was seen in 8 out of 17 (47%) evaluable patients. Severe AGVHD occurred in 3 out of 17 (18%). Clinical CGVHD of all grades developed in 12 out of 17 (70%) evaluable patients. The mean disease-free survival and overall survival were 17 (range: 8-33 months) and 18 months (range: 10-34 months), respectively. In conclusion, alloPBSCT in ANLL is associated with a faster engraftment, no greater incidence of AGVHD, but increased risk of CGVHD. PMID:10414235

  1. Early administration of recombinant erythropoietin improves hemoglobin recovery after reduced intensity conditioned allogeneic stem cell transplantation.

    PubMed

    Ivanov, V; Faucher, C; Mohty, M; Bilger, K; Ladaique, P; Sainty, D; Arnoulet, C; Chabannon, C; Vey, N; Camerlo, J; Bouabdallah, R; Viens, P; Maraninchi, D; Bardou, V J; Esterni, B; Blaise, D

    2005-11-01

    The use of recombinant human erythropoietin (rHuEPO) has been controversial after myeloablative allogeneic Stem cell transplantation (allo-SCT). Reduced intensity conditioning regimens (RIC) offer a novel approach that might translate into a different profile of erythropoietic recovery. We treated 20 consecutive patients with rHuEPO early after matched sibling RIC allo-SCT. Conditioning included fludarabine, busulfan and antithymocyte globulin. EPO treatment was analyzed in terms of toxicity, impact on the frequency of Red blood cell transfusions (RBCT) and kinetics of Hemoglobin recovery within the 60 days post-allo-SCT. Results were compared with 27 matched patients who did not receive rHuEPO. In the first 2 months after allo-SCT all patients receiving rHuEPO (100%) achieved an Hb level > 11 g/dl at a median of 30 (15-35) days post-allo-SCT, as compared to only 63% of the patients not receiving rHuEPO (P = 0.007) at a median of 35 (20-55) days (P = 0.03). A total of 70% (95% CI, 50-90) of rHuEPO patients maintained an Hb over 11 g/dl in the second month as compared to only 19% (95% CI, 4-34) in the other group (P = 0.0004). For patients receiving RBCT, the use of rHuEPO was associated with a trend towards reduced RBCT requirements. This pilot study suggests a potential benefit of early administration of rHuEPO after RIC allo-SCT on early erythropoietic recovery. PMID:16151421

  2. Dynamic of bone marrow fibrosis regression predicts survival after allogeneic stem cell transplantation for myelofibrosis.

    PubMed

    Kröger, Nicolaus; Zabelina, Tatjana; Alchalby, Haefaa; Stübig, Thomas; Wolschke, Christine; Ayuk, Francis; von Hünerbein, Natascha; Kvasnicka, Hans-Michael; Thiele, Jürgen; Kreipe, Hans-Heinrich; Büsche, Guntram

    2014-06-01

    We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation. PMID:24589549

  3. Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mensen, Angela; Oh, Youngseong; Becker, Sonya C; Hemmati, Philipp G; Jehn, Christian; Westermann, Jörg; Szyska, Martin; Göldner, Henning; Dörken, Bernd; Scheibenbogen, Carmen; Arnold, Renate; Na, Il-Kang

    2015-11-01

    Long-term survival after allogeneic hematopoietic stem cell transplantation requires intact immunosurveillance, which is hampered by lymphoid organ damage associated with conditioning therapy, graft-versus-host disease, and immunosuppression. Our study aimed to identify the mechanisms contributing to sustained low memory B cell numbers after transplantation. Peripheral B and T cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to 1 year after transplantation. Apoptosis of B cells after CD40/TLR-9, CD40/BCR, and CD40/BCR/TLR-9-dependent stimulation and drug efflux capacity were analyzed. One half of the patients suffered from infections after day 180. All patients had strongly diminished CD27(+) memory B cells despite already normalized total B cell numbers and fully recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon CD40/TLR-9-dependent activation, B cells underwent significantly increased apoptosis paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9-dependent activation. Drug efflux capacity of naïve B cells was diminished in cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that B cell survival and migration and T cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on the cellular level and should

  4. 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

  5. Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation.

    PubMed

    Zhang, Xiao-Hui; Wang, Qian-Ming; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Zhang, Yuan-Yuan; Mo, Xiao-Dong; Chen, Yao; Wang, Yu; Chang, Ying-Jun; Xu, Lan-Ping; Liu, Kai-Yan; Huang, Xiao-Jun

    2016-10-01

    Intracranial hemorrhage (ICH) is one of the most life-threatening neurological complications after allogeneic hematopoietic stem cell transplantation. Although cerebral complications and its causes after allo-HSCT are well documented, assessment of the incidence and risk factors of intracranial hemorrhage following allo-HSCT are less discussed. A nested case-control study was conducted involving 160 subjects drawn from 2169 subjects who underwent HSCT at Peking University People's Hospital between 2004 and 2014. Thirty-two patients (1.5 %) with ICH were identified, and 128 controls were matched for age, gender, transplantation type, and time of transplantation. Intracranial hemorrhage was identified by CT scan and/or MRI by searching hospital records. Among the 32 ICH patients, 27 (82.9 %) developed intraparenchymal hemorrhages (IPH), 2 cases (5.7 %) suffered subdural hematomas (SDH), and 3 cases (8.6 %) had multiple hemorrhage lesions in the brain parenchyma. The median time of appearance for cerebral hemorrhages was 147.5 days. Multivariate analysis showed that systemic infections (hazard ratio 2.882, 95 % confidence interval 1.231-6.746), platelet count (5.894, 1.145-30.339), and fibrinogen levels (3.611, 1.528-8.532) were independent risk factors for intracranial hemorrhage among HSCT patients. The cumulative survival rate in the intracranial hemorrhage and control groups were 43.3 and 74.7 % (P = .001), respectively. Intracranial hemorrhage is associated with high mortality and a decreased overall survival rate. Systemic infections, platelet count, and fibrinogen levels were individual independent risk factors. PMID:27485455

  6. 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. PMID:24462984

  7. Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody-Mediated Operational Tolerance Induction.

    PubMed

    Calderon, D; Prot, M; You, S; Marquet, C; Bellamy, V; Bruneval, P; Valette, F; de Almeida, P; Wu, J C; Pucéat, M; Menasché, P; Chatenoud, L

    2016-02-01

    Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC-derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20-25 days. Recipients treated with CD3 antibody showed long-term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self-limited. Regulatory CD4(+)FoxP3(+) T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF-β and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression. PMID:26492394

  8. 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

  9. ALK-positive inflammatory myofibroblastic tumor harboring ALK gene rearrangement, occurring after allogeneic stem cell transplant in an adult male.

    PubMed

    Vroobel, Katherine; Judson, Ian; Dainton, Melissa; McCormick, Alison; Fisher, Cyril; Thway, Khin

    2016-08-01

    Inflammatory myofibroblastic tumor arose as a defined neoplasm from the disparate group of tumors (both neoplastic and inflammatory) originally described as inflammatory pseudotumors. The morphologic features are well described, and 50-60% of cases are associated with fusions of the anaplastic lymphoma kinase (ALK) gene. We describe an inflammatory myofibroblastic tumor in the lower abdominal wall of an adult male, which occurred 88days after he received an allogeneic stem cell transplant for T-lymphoblastic lymphoma, and which was positive for ALK immunohistochemistry and showed ALK gene rearrangement by fluorescence in situ hybridization. Two other cases are reported in the post-stem cell transplant setting, but both occurred in children and did not have molecular analysis performed. The etiology remains unclear, but may be due to immune dysregulation caused by any combination of prior chemotherapy, radiotherapy and immune suppression. These neoplasms should be considered as a rare consequence of allogeneic stem cell transplantation and referral to a specialist sarcoma center for further management may be required. PMID:27155927

  10. Impact of stem cell source and conditioning regimen on erythrocyte recovery kinetics after allogeneic haematopoietic stem cell transplantation from an ABO-incompatible donor.

    PubMed

    Kanda, Yoshinobu; Tanosaki, Ryuji; Nakai, Kunihisa; Saito, Takeshi; Ohnishi, Mutsuko; Niiya, Hironari; Chizuka, Aki; Yakushijin, Kimikazu; Urahama, Norinaga; Ueda, Kyoji; Iijima, Kimiko; Ando, Toshihiko; Matsubara, Hiroshi; Kami, Masahiro; Makimoto, Atsushi; Kobayashi, Yukio; Tobinai, Kensei; Mineishi, Shin; Takaue, Yoichi

    2002-07-01

    We evaluated erythrocyte recovery in 121 allogeneic haematopoietic stem cell transplantation (HSCT) recipients. There were 35 major and minor ABO-incompatible transplants, respectively, including 10 bi-directionally ABO-incompatible transplants. The use of peripheral blood stem cells facilitated erythrocyte recovery, regardless of the presence or absence of major ABO-incompatibility, and was associated with a frequent detection of anti-host isohaemagglutin early after minor ABO-incompatible transplantation, which was not associated with clinically relevant haemolysis. The use of a reduced-intensity regimen combining a purine analogue and busulphan did not delay erythrocyte recovery after major ABO-incompatible transplantation, suggesting this regimen had a strong activity against host plasma cell. PMID:12100136

  11. Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab.

    PubMed

    Unal, Sule; Sag, Erdal; Kuskonmaz, Baris; Kesici, Selman; Bayrakci, Benan; Ayvaz, Deniz C; Tezcan, Ilhan; Yalnızoglu, Dilek; Uckan, Duygu

    2014-05-01

    Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up. PMID:24307660

  12. Ocular Graft Versus Host Disease Following Allogeneic Stem Cell Transplantation: A Review of Current Knowledge and Recommendations

    PubMed Central

    Nassiri, Nariman; Eslani, Medi; Panahi, Nekoo; Mehravaran, Shiva; Ziaei, Alireza; Djalilian, Ali R.

    2013-01-01

    Graft versus host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT). Ocular GVHD develops in approximately 40-60% of patients following allo-SCT and its most common clinical manifestations include keratoconjunctivitis sicca and cicatricial conjunctivitis. Ocular GVHD may lead to severe ocular surface disease, which can significantly diminish quality of life and restrict daily activities. It is thus important to monitor the condition closely since with timely diagnosis, irreversible damage can be avoided. The current review will focus on updated information regarding ocular GVHD. PMID:24653823

  13. Antiretroviral-Free HIV-1 Remission and Viral Rebound Following Allogeneic Stem Cell Transplantation: A Report of Two Cases

    PubMed Central

    Henrich, Timothy J.; Hanhauser, Emily; Marty, Francisco M.; Sirignano, Michael N.; Keating, Sheila; Lee, Tzong-Hae; Robles, Yvonne P.; Davis, Benjamin T.; Li, Jonathan Z.; Heisey, Andrea; Hill, Alison L.; Busch, Michael P.; Armand, Philippe; Soiffer, Robert J.; Altfeld, Marcus; Kuritzkes, Daniel R.

    2014-01-01

    Background It is unknown if the reduction in HIV-1 reservoirs observed following allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 remission. Objective To characterize HIV-1 reservoirs in blood and tissues, and to perform analytical antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained antiretroviral-free HIV-1 remission. Design Characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption. Setting Tertiary care center. Patients Two HIV-infected men with undetectable HIV-1 following allogeneic HSCT for hematologic malignancies. Measurements Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption. Results No HIV-1 was detected from peripheral blood or rectal mucosa prior to analytical treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 to 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia with the development of acute retroviral syndrome within one to two weeks of the most recent negative viral load measurement. One patient developed new efavirenz resistance after re-initiation of antiretroviral therapy. Re-initiation of active therapy led to viral decay and resolution of symptoms in both patients. Limitations The study was limited to 2 patients. Conclusions Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. Defining the nature and half-life of such reservoirs is essential in order to achieve durable antiretroviral-free HIV-1 remission. PMID:25047577

  14. Pure Red Cell Aplasia in Major ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Severe Pancytopenia.

    PubMed

    Aung, Fleur M; Lichtiger, Benjamin; Rondon, Gabriela; Yin, C Cameron; Alousi, Amin; Ahmed, Sairah; Andersson, Borje S; Bashir, Qaiser; Ciurea, Stefan O; Hosing, Chitra; Jones, Roy; Kebriaei, Partow; Khouri, Issa; Nieto, Yago; Oran, Betul; Parmar, Simrit; Qazilbash, Muzaffar; Shah, Nina; Shpall, Elizabeth J; Champlin, Richard E; Popat, Uday

    2016-05-01

    In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/μL or requiring granulocyte colony-stimulating factor, platelets < 50 K/μL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients. PMID:26921820

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

    PubMed

    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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Prophylactic antiviral therapy in allogeneic hematopoietic stem cell transplantation in hepatitis B virus patients

    PubMed Central

    Liao, Ya-Ping; Jiang, Jia-Lu; Zou, Wai-Yi; Xu, Duo-Rong; Li, Juan

    2015-01-01

    AIM: To investigate the timing, safety and efficacy of prophylactic antiviral therapy in patients with hepatitis B virus (HBV) infection undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: This prospective study recruited a total of 57 patients diagnosed with malignant hematological diseases and HBV infection at the First Affiliated Hospital of Sun Yat-sen University between 2006 and 2013. The patients were classified as hepatitis B surface antigen (HBsAg)-positive or HBsAg-negative/ antiHBc-positive. Patients were treated with chemotherapy followed by antiviral therapy with nucleoside analogues. Patients underwent allo-HSCT when serum HBV DNA was < 103 IU/mL. Following allo-HSCT, antiviral therapy was continued for 1 year after the discontinuation of immunosuppressive therapy. A total of 105 patients who underwent allo-HSCT and had no HBV infection were recruited as controls. The three groups were compared for incidence of graft-vs-host disease (GVHD), drug-induced liver injury, hepatic veno-occlusive disease, death and survival time. RESULTS: A total of 29 of the 41 subjects with chronic GVHD exhibited extensive involvement and 12 exhibited focal involvement. Ten of the 13 subjects with chronic GVHD in the HBsAg(-)/hepatitis B core antibody(+) group exhibited extensive involvement and 3 exhibited focal involvement. Five of the 10 subjects with chronic GVHD in the HBsAg(+) group exhibited extensive involvement and 5 exhibited focal involvement. The non HBV-infected group did not differ significantly from the HBsAg-negative/antiHBc-positive and the HBsAg-positive groups which were treated with nucleoside analogues in the incidence of graft-vs-host disease (acute GVHD; 37.1%, 46.9% and 40%, respectively; P = 0.614; chronic GVHD; 39%, 40.6% and 40%, respectively; P = 0.98), drug-induced liver injury (25.7%, 18.7% and 28%, respectively; P = 0.7), death (37.1%, 40.6% and 52%, respectively; P = 0.4) and survival times (P = 0.516). One

  1. 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

  2. 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

  3. Leukemia cell mobilization with G-CSF plus plerixafor during busulfan-fludarabine conditioning in allogeneic stem cell transplantation

    PubMed Central

    Thall, Peter F.; Zeng, Zhihong; Shpall, Elizabeth; Ciurea, Stefan; Kebriaei, Partow; Alousi, Amin; Popat, Uday; Anderlini, Paolo; Nieto, Yago; Parmar, Simrit; Qiao, Wei; Chen, Julianne; Rondon, Gabriela; McMullin, Becky; Wang, Rui-Yu; Lu, Hongbo; Schober, Wendy; Woodworth, Glenda; Gulbis, Alison; Cool, Rita; Andreeff, Michael; Champlin, Richard

    2015-01-01

    We hypothesized that during conditioning chemotherapy for allogeneic stem cell transplant (allo-SCT), disruption of stromal-leukemia interactions using granulocyte-colony stimulating factor (G-CSF) in combination with the CXCR4-specific inhibitor plerixafor, may promote release of leukemic cells from the niche and increase tumor elimination. In a phase 1/2 investigation, we treated 45 AML/MDS/CML patients (34 AML, 7 MDS, and 4 CML) with G-CSF (10 μg/kg daily for 6 days starting on day −9) plus plerixafor (doses of 0, 80, 160 or 240 μg/kg daily for 4 days starting on day −7) along with the busulfan-fludarabine (Bu-Flu) conditioning regimen. In the phase 1 part, we determined that G-CSF plus plerixafor is safe in this setting. We compared clinical effects and outcomes of AML/MDS study patients (n = 40) to 164 patients from a historical data set who received Bu-Flu alone prior to allo-SCT by stratifying on cytogenetics and disease status to correct for bias. Study patients had increased myeloid chimerism and lower rates of GvHD. There was no significant difference in relapse free survival or overall survival. The G-CSF plus plerixafor combination increased circulating white blood cells, CD34+ cells, and CXCR4+ cells, and preferentially mobilized FISH+ leukemic cells. ClinicalTrials.gov identifier is NCT00822770. PMID:25867648

  4. Engraftment kinetics and hematopoietic chimerism after reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation.

    PubMed

    Blau, I W; Schmidt-Hieber, Martin; Leschinger, N; Göldner, H; Knauf, W; Hopfenmüller, W; Thiel, E; Blau, O

    2007-08-01

    Reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation (SCT) was introduced several years ago. Although its feasibility has recently been proven, only limited data are available on myelotoxicity, engraftment kinetics, and the significance of hematopoietic chimerism using this novel conditioning regimen. To clarify these open questions, we analyzed 27 patients with various hematological diseases, who received allogeneic SCT preceded by fludarabine/treosulfan conditioning. Further assessment endpoints included graft-vs-host disease (GvHD), mortality, and overall survival (OS). Allogeneic SCT was followed by neutropenia (absolute neutrophil count < or = 0.5 x 10(9)/l) and thrombocytopenia (platelets < or = 20 x 10(9)/l) in all patients. All patients showed stable neutrophil engraftment, and all except one had stable platelet engraftment. Grades II-IV acute GvHD was found in 48% of patients, whereas 52% developed chronic GvHD. The treatment-related mortality on day +100, 1 year after SCT, and at the last follow-up was 11, 26, and 33%, respectively. We found complete chimerism rates of 46, 57, and 72% on days +28, +56, and at the last follow-up or before death, respectively. The underlying malignancy tended to relapse more frequently in patients with mixed chimerism than in those with complete chimerism on day +28 as well as on day +56 (not significant). Additionally, no significant association was found between hematopoietic chimerism and donor type, GvHD, or OS, respectively. We conclude that reduced-intensity conditioning with fludarabine and treosulfan before allogeneic SCT is myeloablative, provides stable engraftment, and leads to complete chimerism in the majority of patients. PMID:17468869

  5. 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

  6. 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

  7. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis

    PubMed Central

    Kumar, Shaji; Zhang, Mei-Jie; Li, Peigang; Dispenzieri, Angela; Milone, Gustavo A.; Lonial, Sagar; Krishnan, Amrita; Maiolino, Angelo; Wirk, Baldeep; Weiss, Brendan; Freytes, César O.; Vogl, Dan T.; Vesole, David H.; Lazarus, Hillard M.; Meehan, Kenneth R.; Hamadani, Mehdi; Lill, Michael; Callander, Natalie S.; Majhail, Navneet S.; Wiernik, Peter H.; Nath, Rajneesh; Kamble, Rammurti T.; Vij, Ravi; Kyle, Robert A.; Gale, Robert Peter

    2011-01-01

    Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001). PMID:21690560

  8. MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice

    PubMed Central

    Hirata, Yuichi; Li, Hao-Wei; Takahashi, Kazuko; Ishii, Hiroshi; Sykes, Megan; Fujisaki, Joji

    2015-01-01

    NK cells resist engraftment of syngeneic and allogeneic bone marrow (BM) cells lacking major histocompatibility (MHC) class I molecules, suggesting a critical role for donor MHC class I molecules in preventing NK cell attack against donor hematopoietic stem and progenitor cells (HSPCs), and their derivatives. However, using high-resolution in vivo imaging, we demonstrated here that syngeneic MHC class I knockout (KO) donor HSPCs persist with the same survival frequencies as wild-type donor HSPCs. In contrast, syngeneic MHC class I KO differentiated hematopoietic cells and allogeneic MHC class I KO HSPCs were rejected in a manner that was significantly inhibited by NK cell depletion. In vivo time-lapse imaging demonstrated that mice receiving allogeneic MHC class I KO HSPCs showed a significant increase in NK cell motility and proliferation as well as frequencies of NK cell contact with and killing of HSPCs as compared to mice receiving wild-type HSPCs. The data indicate that donor MHC class I molecules are required to prevent NK cell-mediated rejection of syngeneic differentiated cells and allogeneic HSPCs, but not of syngeneic HSPCs. PMID:26544200

  9. [Alleviation of palmoplantar pustulosis associated with adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation].

    PubMed

    Akasaka, Hiroshi; Imaizumi, Kisako; Sakane, Emiko; Tsunemine, Hiroko; Ito, Kiminari; Kodaka, Taiichi; Matsumoto, Mayumi; Matsuoka, Masao; Takahashi, Takayuki

    2012-08-01

    A 68-year-old female with palmoplantar pustulosis was referred to our hospital in July, 2009 because of liver dysfunction, a positive test for HTLV-1, and circulating abnormal lymphocytes with irregularly shaped nuclei. A diagnosis of acute type adult T cell leukemia/lymphoma (ATLL) was made based on generalized lymph node swelling and high levels of serum LDH, in addition to the findings described above. The associated palmoplantar pustulosis responded to some extent to antibiotics, steroid ointment, and narrow band UBV light irradiation. For ATLL, she was serially treated with CHOP chemotherapy, an LSG 15 protocol, and CytaBOM protocol with consequent partial remission. These chemotherapies did not affect the palmoplantar pustulosis. For ATLL in partial remission, we performed allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from a related donor (HTLV-1-negative) with a conditioning regimen consisting of fludarabine, melphalan, and total body irradiation with 3 Gy in February, 2010. After the engraftment of donor hematopoietic cells, ATLL cells disappeared and the patient currently (as of April, 2012) remains in complete remission (CR). The residual palmoplantar pustulosis was further improved soon after allo-PBSCT and disappeared on Day 84 after transplantation. This refractory skin disease has also been in CR to date. PMID:22975820

  10. Co-transplantation of syngeneic mesenchymal stem cells improves survival of allogeneic glial-restricted precursors in mouse brain.

    PubMed

    Srivastava, Amit K; Bulte, Camille A; Shats, Irina; Walczak, Piotr; Bulte, Jeff W M

    2016-01-01

    Loss of functional cells from immunorejection during the early post-transplantation period is an important factor that reduces the efficacy of stem cell-based therapies. Recent studies have shown that transplanted mesenchymal stem cells (MSCs) can exert therapeutic effects by secreting anti-inflammatory and pro-survival trophic factors. We investigated whether co-transplantation of MSCs could improve the survival of other transplanted therapeutic cells. Allogeneic glial-restricted precursors (GRPs) were isolated from the brain of a firefly luciferase transgenic FVB mouse (at E13.5 stage) and intracerebrally transplanted, either alone, or together with syngeneic MSCs in immunocompetent BALB/c mice (n=20) or immunodeficient Rag2(-/-) mice as survival control (n=8). No immunosuppressive drug was given to any animal. Using bioluminescence imaging (BLI) as a non-invasive readout of cell survival, we found that co-transplantation of MSCs significantly improved (p<0.05) engrafted GRP survival. No significant change in signal intensities was observed in immunodeficient Rag2(-/-) mice, with transplanted cells surviving in both the GRP only and the GRP+MSC group. In contrast, on day 21 post-transplantation, we observed a 94.2% decrease in BLI signal intensity in immunocompetent mice transplanted with GRPs alone versus 68.1% in immunocompetent mice co-transplanted with MSCs and GRPs (p<0.05). Immunohistochemical analysis demonstrated a lower number of infiltrating CD45, CD11b(+) and CD8(+) cells, reduced astrogliosis, and a higher number of FoxP3(+) cells at the site of transplantation for the immunocompetent mice receiving MSCs. The present study demonstrates that co-transplantation of MSCs can be used to create a microenvironment that is more conducive to the survival of allogeneic GRPs. PMID:26515691

  11. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Luznik, Leo

    2010-01-01

    Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloHSCT. High-dose, post-transplantation Cy facilitates partially HLA-mismatched HSCT without severe GVHD and is effective as sole prophylaxis of GVHD after HLA-matched alloHSCT. By reducing the morbidity and mortality of alloHSCT, post-transplantation Cy may expand the applications of this therapy to the treatment of autoimmune diseases and non-malignant hematologic disorders such as sickle cell disease. PMID:20066512

  12. Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Al-Homsi, Ahmad Samer; Feng, Yuxin; Duffner, Ulrich; Al Malki, Monzr M; Goodyke, Austin; Cole, Kelli; Muilenburg, Marlee; Abdel-Mageed, Aly

    2016-09-01

    Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. Although current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor, possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD. Herein, we review the current understanding of the effects of bortezomib in vitro and in animal models and summarize the clinical data relevant to its use in the prevention and treatment of GvHD. We conclude with an outline of the remaining challenges and opportunities to optimize bortezomib's potential role in this setting. PMID:27224851

  13. 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

  14. L-asparaginase-based regimens followed by allogeneic hematopoietic stem cell transplantation improve outcomes in aggressive natural killer cell leukemia.

    PubMed

    Jung, Ki Sun; Cho, Su-Hee; Kim, Seok Jin; Ko, Young Hyeh; Kang, Eun-Suk; Kim, Won Seog

    2016-01-01

    Aggressive nature killer cell leukemia (ANKL) is a mature NK-T cell lymphoma with worse prognosis, but optimal treatment is unclear. Therefore, we analyzed the efficacy of L-asparaginase-based regimens for ANKL patients. Twenty-one patients who received dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) or etoposide, ifosfamide, dexamethasone, and L-asparaginase (VIDL) chemotherapy at Samsung Medical Center were selected. The overall response rate for all patients was 33% (7/21); 38% (5/13) in SMILE and 40% (2/5) in VIDL, respectively. The median progression-free survival was 3.9 months (95% CI 0.0-8.1 months) and median overall survival was 7.0 months (95% CI 2.3-11.7 months). Treatment response (P = 0.001), hematopoietic stem cell transplantation (HSCT) (P = 0.007) and negative conversion of Epstein-Barr virus (EBV) DNA titer after treatment (P = 0.004) were significantly associated with survival. Thus, L-asparaginase-based regimens followed by allogeneic HSCT seem to improve the outcome for ANKL patients. PMID:27091029

  15. Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event.

    PubMed

    Burns, David M; Tierney, Rose; Shannon-Lowe, Claire; Croudace, Jo; Inman, Charlotte; Abbotts, Ben; Nagra, Sandeep; Fox, Christopher P; Chaganti, Sridhar; Craddock, Charles F; Moss, Paul; Rickinson, Alan B; Rowe, Martin; Bell, Andrew I

    2015-12-17

    Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B-cell system. Although many allo-HSCT recipients maintain low or undetectable levels of EBV DNA posttransplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated posttransplant lymphoproliferative disease. Intriguingly, this high-level EBV reactivation typically arises in the first 3 months posttransplant, at a time when the peripheral blood contains low numbers of CD27+ memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B-cell reconstitution in a cohort of allo-HSCT patients for up to 12 months posttransplant. In patients with low or undetectable levels of EBV, the circulating B-cell pool consisted predominantly of transitional and naive cells, with a marked deficiency of CD27+ memory cells which lasted >12 months. However, among patients with high EBV loads, there was a significant increase in both the proportion and number of CD27+ memory B cells. Analysis of sorted CD27+ memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B-cell growth transformation, had a plasmablastic phenotype, and frequently expressed the proliferation marker Ki-67. These findings suggest that high-level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27+ B lymphoblasts in the peripheral blood. PMID:26450987

  16. Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event

    PubMed Central

    Burns, David M.; Tierney, Rose; Shannon-Lowe, Claire; Croudace, Jo; Inman, Charlotte; Abbotts, Ben; Nagra, Sandeep; Fox, Christopher P.; Chaganti, Sridhar; Craddock, Charles F.; Moss, Paul; Rickinson, Alan B.; Rowe, Martin

    2015-01-01

    Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B-cell system. Although many allo-HSCT recipients maintain low or undetectable levels of EBV DNA posttransplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated posttransplant lymphoproliferative disease. Intriguingly, this high-level EBV reactivation typically arises in the first 3 months posttransplant, at a time when the peripheral blood contains low numbers of CD27+ memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B-cell reconstitution in a cohort of allo-HSCT patients for up to 12 months posttransplant. In patients with low or undetectable levels of EBV, the circulating B-cell pool consisted predominantly of transitional and naive cells, with a marked deficiency of CD27+ memory cells which lasted >12 months. However, among patients with high EBV loads, there was a significant increase in both the proportion and number of CD27+ memory B cells. Analysis of sorted CD27+ memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B-cell growth transformation, had a plasmablastic phenotype, and frequently expressed the proliferation marker Ki-67. These findings suggest that high-level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27+ B lymphoblasts in the peripheral blood. PMID:26450987

  17. Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations.

    PubMed

    Wu, Qiu-Ling; Liu, Xiao-Yun; Nie, Di-Min; Zhu, Xia-Xia; Fang, Jun; You, Yong; Zhong, Zhao-Dong; Xia, Ling-Hui; Hong, Mei

    2015-08-01

    Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK cells, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4(+) and CD8(+) Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations. PMID:26223913

  18. The Incidence and Severity of Oral Mucositis among Allogeneic Hematopoietic Stem Cell Transplantation Patients: A Systematic Review.

    PubMed

    Chaudhry, Hafsa M; Bruce, Alison J; Wolf, Robert C; Litzow, Mark R; Hogan, William J; Patnaik, Mrinal S; Kremers, Walter K; Phillips, Gordon L; Hashmi, Shahrukh K

    2016-04-01

    Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen correlates with the incidence and severity of OM, but no studies have analyzed this relationship among various conditioning regimens. We performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and analyzed this association. A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Cochrane CRCT, Cochrane DSR, Scopus) from 1990 to 2014 for studies of OM in allogeneic HSCT patients was conducted. Professional societies' meeting abstracts were also searched. Grade of OM was analyzed based on the World Health Organization (WHO) or National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events scales. Severe mucositis was defined as either grades 2 to 4 or grades 3 and 4, depending on the studies' definition of severity. Cohorts were analyzed based on regimen intensity; ie, reduced-intensity conditioning (RIC) (including nonmyeloablative) and myeloablative (MA). Random effect (RE) and standard logistic models weighted by the number of patients in each cohort were used for comparisons. A total of 624 studies were generated from the search. Of the 395 patients in 8 eligible MA regimen studies, 73.2% experienced any OM, whereas in 245 patients in the 6 eligible RIC regimen studies, 86.5% experienced any OM (chi-square P < .0001; RE, P = .05). Severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% of RIC patients (chi-square, P = .0421; RE, P < .01). In comparing graft-versus-host disease (GVHD) prophylaxis, only 55.4% of patients receiving nonmethotrexate regimens experienced OM; this was lower (chi-square, P < .0001; RE, P = .06) than that found among patients who received methotrexate (83.4%), either standard or reduced dose. Besides NCI and WHO

  19. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease.

    PubMed

    Strocchio, Luisa; Zecca, Marco; Comoli, Patrizia; Mina, Tommaso; Giorgiani, Giovanna; Giraldi, Eugenia; Vinti, Luciana; Merli, Pietro; Regazzi, Mario; Locatelli, Franco

    2015-06-01

    Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD. PMID:25818248

  20. Bone Density and Structure in Long-Term Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

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

    2015-01-01

    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 5–26 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), 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 vs. 0.23 ± 0.92; p<0.001), vs. reference participants; BMI Z-scores did not differ. AlloHSCT survivors had lower trabecular vBMD [−1.05 (95% CI −1.33, −0.78), p<0.001], cortical Zp [−0.63 (−0.91, −0.35), p<0.001], and muscle [−1.01 (−1.30, −0.72), p<0.001] Z-scores and greater fat [0.82 (0.54,1.11), p<0.001] Z-scores, vs. 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 vs. −0.49 ± 0.88; p=0.01) and muscle (−1.34 ± 1.42 vs. −0.34 ± 0.87; p<0.01) Z-scores. Growth hormone deficiency (GHD) was associated with lower Zp Z-scores (−1.64 ± 2.47 vs. −0.28 ± 1.24; p=0.05); however, muscle differences were not significant (−1.69 ± 1.84 vs. −0.78 ± 1.01; p=0.09). History of graft vs. 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 GHD were significant risk factors for musculoskeletal deficits. Future studies are needed to determine the metabolic and fracture

  1. 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

  2. Symptom distress predicts long-term health and well-being in allogeneic stem cell transplantation survivors.

    PubMed

    Bevans, Margaret F; Mitchell, Sandra A; Barrett, John A; Bishop, Michael R; Childs, Richard; Fowler, Daniel; Krumlauf, Michael; Prince, Patricia; Shelburne, Nonniekaye; Wehrlen, Leslie; Yang, Li

    2014-03-01

    The number of survivors after allogeneic hematopoietic stem cell transplantation (HSCT) continues to increase, yet their survivorship experience has not been fully characterized. This study examines the health status and health-related quality of life (HRQL) of HSCT survivors. The aims of the study were to: (1) explore the baseline and change over time in these health outcomes, and (2) characterize subgroups experiencing adverse outcomes. In this longitudinal study, adults who survived >3 years from date of allogeneic HSCT completed a series of patient-reported outcome measures annually, including measures of health status, HRQL, and symptoms. Data were analyzed using hierarchical linear modeling. Subjects (N = 171) were on average 44 (±13.5) years of age and primarily male (62.6%); 40% were Hispanic. Mean scores for physical and mental health and HRQL were preserved relative to population norms. Hierarchical linear modeling revealed no significant change in the mean trajectories of these outcomes, although significant between-individual variability was observed. When controlling for demographic and clinical factors, physical symptom distress negatively affected all outcomes. The impact of symptom distress on physical health varied based on time since HSCT; impairment in physical health was greatest in survivors experiencing high symptom distress and who were within the first decade post transplantation. Extended treatment with systemic immunosuppressive therapy also predicted inferior physical health. These findings suggest that patient-centered outcomes are preserved relative to normative values and are generally stable after allogeneic HSCT, although survivors with persistent symptoms and those receiving systemic immunosuppression experience impairments in health status and HRQL. PMID:24355521

  3. ABCG2, Cytogenetics, and Age Predict Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission.

    PubMed

    Damiani, Daniela; Tiribelli, Mario; Geromin, Antonella; Cerno, Michela; Zanini, Francesca; Michelutti, Angela; Fanin, Renato

    2016-09-01

    Recent studies have shown that ABGG2 protein overexpression in acute myeloid leukemia (AML) may be associated with poor response to therapy and increased relapse risk. Few data are available in patients with AML undergoing allogeneic stem cell transplantation (SCT), particularly when in complete remission (CR). We analyzed 105 patients with AML who underwent allogeneic SCT in CR evaluating the role of ABCG2 and other pretransplantation features on subsequent transplantation outcomes. Factors negatively associated with leukemia-free survival (LFS) were unfavorable cytogenetics (3-year LFS 48% versus 80%, P = .0035) and ABCG2 positivity (65% versus 80%, P = .045). Three-year cumulative incidence of relapse (CIR) in the whole population was 20%; a higher incidence of relapse was associated with adverse cytogenetics (41% versus 16%, P = .018), ABCG2 overexpression (29% versus 15%, P = .04), and, marginally, age > 50 years (30% versus 14%, P = .06). We grouped patients according to the combination of these 3 risk factors: no patient relapsed within 3 years from SCT in the group without risk factors, whereas the 3-year CIR was 12% (95% confidence interval [CI], 2% to 25%) in the group with 1 risk factor and 47% (95% CI, 31% to 70%) in patients with 2 or 3 risk factors (P = .00005). In conclusion, allogeneic SCT does not seem to abrogate the negative prognosis associated with ABCG2 overexpression at diagnosis, specifically in terms of a higher relapse risk. ABCG2, age, and cytogenetics can predict AML relapse after SCT in patients who undergo transplantation while in CR. PMID:27178373

  4. The Prevalence of Antifungal Agents Administration in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study

    PubMed Central

    Kargar, Mona; Ahmadvand, Alireza; Ahmadvand, Milad; Hadjibabaie, Molouk; Gholami, Kheirollah; Khoee, Seyed Hamid; Javadi, Mohammad Reza; Ghavamzadeh, Ardeshir

    2013-01-01

    Background Invasive fungal infections (IFIs) are chief infectious complications in patients undergoing hematopoietic stem cell transplantation (HSCT). However, the diagnosis of fungal infections is difficult, and often empiric treatment initiates. Since there is no data available on the prevalence of antifungal drugs administration in allogeneic HSCT recipients in Iran, we decided to conduct this study. Methods This study was a retrospective review of records of patients who received allogeneic HSCT in the Hematology-Oncology, Bone Marrow Transplantation center at Shariati Hospital in Tehran, between August 2009 and August 2010. Results Sixty (73.1%) patients consist of 41 men (68.3%) with mean age of 26.3 (± 1.2) years received allogeneic HSCT. Patients received prophylaxis with fulconazole however; in 28 patients (46.7%) it was switched to low dose amphotericin B. Fifteen patients (25%) received treatment with antifungal agents. Amphotericin B was the empiric agent administered. In 3 patients treatment was switched to voriconazole. Neither positive culture nor direct microscopic evidence was available from the obtained specimen. Only in one patient the result of serum galactomannan assay was positive. There were no significant differences in neutropenia duration (P value: 0.54), length of hospital stay (P value: 0.27) and number of patients developed graft versus host disease (P value: 0.07) between patients received antifungal agents with those who did not receive treatment. Conclusion In this study HSCT recipients received antifungal agents for prophylaxis. Twenty five percent of patients received treatment with antifungal agents empirically. Improvement in diagnosis of these infections can be helpful and lead to targeted therapy. We suggest larger prospective trials for better assessment of antifungal agent administration. PMID:24505528

  5. Review of Stem-Cell Transplantation for Myelodysplastic Syndromes in Older Patients in the Context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome Emanating From the Centers for Medicare and Medicaid Services

    PubMed Central

    Giralt, Sergio A.; Horowitz, Mary; Weisdorf, Daniel; Cutler, Corey

    2011-01-01

    Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem-cell disorders that result in varying degrees of cytopenia and risk of transformation into acute leukemia. Allogeneic stem-cell transplantation (SCT) is the only known cure for this disease. The treatment is routinely used for younger patients, but only a minority of patients older than the age of 60 undergo this procedure. The overall MDS incidence is 3.3 per 100,000, but the incidence in patients older than age 70 is between 15 and 50 per 100,000. The median age at presentation is 76 years. Medicare-age patients 65 or older represent 80% of the total population receiving an MDS diagnosis. In the United States, one of the obstacles to SCT for older patients with MDS has been lack of third party reimbursement. On August 4, 2010, the Centers for Medicare and Medicaid Services released their Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome. This memo states: “Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below…. ” In this review, we will summarize what is known regarding the role of allogeneic SCT in older patients as well as other elements that should be included within clinical trials that can provide the evidence necessary to demonstrate that allogeneic SCT should be a covered benefit for Medicare beneficiaries. PMID:21220586

  6. 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

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

    PubMed

    Li, Ya-Ting; Xie, Ming-Kun; Wu, Jin

    2014-11-01

    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

  8. Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

    PubMed

    Mayo, S; Messner, H A; Rourke, S B; Howell, D; Victor, J C; Kuruvilla, J; Lipton, J H; Gupta, V; Kim, D D; Piescic, C; Breen, D; Lambie, A; Loach, D; Michelis, F V; Alam, N; Uhm, J; McGillis, L; Metcalfe, K

    2016-06-01

    Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT. PMID:26926230

  9. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Lorenz, Fryderyk; Marklund, Stefan; Werner, Mårten; Palmqvist, Richard; Wahlin, Björn Engelbrekt; Wahlin, Anders

    2015-01-01

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool. PMID:25605402

  10. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Lorenz, Fryderyk; Marklund, Stefan; Werner, Mårten; Palmqvist, Richard; Wahlin, Björn Engelbrekt; Wahlin, Anders

    2015-01-01

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool. PMID:25605402

  11. Refractory Ascites with Liver Fibrosis Developed in Late Phase Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Patients

    PubMed Central

    Hosoi, Hiroki; Warigaya, Kenji; Murata, Shogo; Mushino, Toshiki; Kuriyama, Kodai; Nishikawa, Akinori; Tamura, Shinobu; Hatanaka, Kazuo; Hanaoka, Nobuyoshi; Muragaki, Yasuteru; Murata, Shinichi; Nakakuma, Hideki; Sonoki, Takashi

    2016-01-01

    We report cases of three patients of refractory ascites without other fluid retention that occurred around five months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). All three patients expired and postmortem examinations revealed unexpected liver fibrosis lacking histological evidences of graft-versus-host-disease (GVHD). The three patients showed normal hepatic function and size before transplantation. During their clinical courses, serum biochemistry test showed no elevation of hepatic enzymes and bilirubin; however, imaging studies demonstrated hepatic atrophy at the onset of ascites. One of the liver specimens showed bile obstruction, which could be seen in hepatic damage by GVHD. Although ascites resulting from venoocclusive disease in early phase allo-HSCT is well documented, ascites associated with hepatic fibrosis in late phase allo-HCST has not been reported. Further clinico-pathological studies on similar patients should be required to ascertain refractory ascites associated with liver fibrosis after allo-HSCT. PMID:27499838

  12. Which Patients Should Undergo Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes, and When Should We Do It?

    PubMed

    Oran, Betul

    2015-06-01

    Allogeneic hematopoietic stem cell transplantation (SCT) can cure a proportion of patients with myelodysplastic syndromes (MDS). However, treatment related toxicities, graft versus host disease, infectious complications and relapse remain major problems post transplant. Further, recent new developments with innovative drugs including hypomethylating agents (HMA) have extended the therapeutic alternatives for our patients. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reducing early mortality, transplant numbers in MDS patients have significantly increased recently. In the absence of prospective randomized trials emphasis should be put on patient selection and optimization of the pre- and post-transplant treatment in order to achieve long-term disease control and at the same time maintain an adequate quality of life. With better understanding of disease biology and prognosis and with different types of conditioning regimens as well as different graft sources, a transplant strategy should be tailored to the individual host to maximize the benefits of this procedure. PMID:26297277

  13. The use of stimulated granulocyte transfusions to prevent recurrence of past severe infections after allogeneic stem cell transplantation.

    PubMed

    Kerr, J Paul; Liakopolou, Effie; Brown, Jessica; Cornish, Jacqueline M; Fleming, David; Massey, Edwin; Oakhill, Anthony; Pamphilon, Derwood H; Robinson, Stephen P; Totem, April; Valencia, Alexandra M P I; Marks, David I

    2003-10-01

    The predictable neutropenia that follows allogeneic stem cell transplantation (ASCT) may be associated with recurrence of previous life-threatening infection. We describe nine patients with either previous invasive aspergillosis (IA) or considered to be at high risk of developing IA who underwent ASCT with prophylactic granulocyte transfusions. The study group, when compared with a control group, had a significant reduction in the incidence and duration of fevers (P < 0.05) and maximum C-reactive protein (P < 0.05). There were significantly fewer days of neutropenia (P < 0.05). There was also radiological improvement of pulmonary infiltrates in four out of seven assessable patients. No serious toxicity was encountered in donors or recipients. We conclude that prophylactic granulocyte donations can be given safely, and that they significantly reduce the number of days of neutropenia. Further investigation is warranted to determine whether granulocyte donations can prevent the recurrence of IA in patients at risk of fungal infection. PMID:14510952

  14. 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

  15. Allogeneic hematopoietic stem cell transplantation for T-prolymphocytic leukemia: a report from the French society for stem cell transplantation (SFGM-TC).

    PubMed

    Guillaume, Thierry; Beguin, Yves; Tabrizi, Reza; Nguyen, Stéphanie; Blaise, Didier; Deconinck, Eric; Redjoul, Rabah; Cornillon, Jérôme; Guillerm, Gaëlle; Contentin, Nathalie; Sirvent, Anne; Turlure, Pascal; Salmon, Alexandra; Huynh, Anne; François, Sylvie; Peffault de Latour, Régis; Yakoub-Agha, Ibrahim; Mohty, Mohamad

    2015-03-01

    T-prolymphocytic leukemia (T-PLL), a rare aggressive mature T-cell disorder, remains frequently resistant to conventional chemotherapy. Studies have suggested that allogeneic hematopoietic stem cell transplantation (HSCT) might possibly serve to consolidate the response to initial chemotherapy. The current report summarizes the outcome of 27 T-PLL cases identified in the registry in French Society for stem cell transplantation (SFGM-TC). Prior to HSCT, 14 patients were in complete remission (CR), 10 in partial response, three refractory, or in progression. Following HSCT, 21 patients achieved CR as best response. With a median follow-up for surviving patients of 33 (range, 6-103) months, 10 patients are still alive in continuous CR. Overall survival and progression-free survival estimates at 3 yr were 36% (95% CI: 17-54%) and 26% (95% CI: 14-45%), respectively. The relapse incidence after HSCT was 47% occurring at a median of 11.7 (range, 2-24) months. Overall cumulative incidence of transplant-related mortality was 31% at 3 yr. These results suggest that HSCT may allow long-term survival in patients with T-PLL following induction treatment; however, it is associated with a significant rate of toxicity. PMID:25130897

  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. [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

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

    PubMed

    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

    2015-06-01

    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 × 10(5))/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-((18)F)fluoro-3-hydroxymethyl-butyl]guanine ([(18)F]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 [(18)F]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 [(18)F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. PMID:25807290

  19. In Vivo Interleukin-13-Primed Macrophages Contribute to Reduced Alloantigen-Specific T Cell Activation and Prolong Immunological Survival of Allogeneic Mesenchymal Stem Cell Implants.

    PubMed

    Hoornaert, Chloé J; Luyckx, Evi; Reekmans, Kristien; Dhainaut, Maxime; Guglielmetti, Caroline; Le Blon, Debbie; Dooley, Dearbhaile; Fransen, Erik; Daans, Jasmijn; Verbeeck, Louca; Quarta, Alessandra; De Vocht, Nathalie; Lemmens, Evi; Goossens, Herman; Van der Linden, Annemie; Roobrouck, Valerie D; Verfaillie, Catherine; Hendrix, Sven; Moser, Muriel; Berneman, Zwi N; Ponsaerts, Peter

    2016-07-01

    Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue-for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins-is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since "off-the-shelf" cell preparations could be readily available for instant therapeutic intervention following acute injury. Although we confirmed the in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard coculture experiments, allogeneic MSC grafts were irrevocably rejected by the host's immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allogeneic MSC grafts in muscle tissue coincided with the induction of an alternatively activated macrophage phenotype in vivo and a reduced number of alloantigen-reactive IFNγ- and/or IL2-producing CD8(+) T cells compared to nonmodified allografts. Similarly, intracerebral IL13-expressing MSC allografts also exhibited prolonged survival and induction of an alternatively activated macrophage phenotype, although a peripheral T cell component was absent. In summary, this study demonstrates that both innate and adaptive immune responses are effectively modulated in vivo by locally secreted IL13, ultimately resulting in prolonged MSC allograft survival in both muscle and brain tissue. Stem Cells 2016;34:1971-1984. PMID:26992046

  20. 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

  1. The use of cytokine-stimulated healthy donors in allogeneic stem cell transplantation.

    PubMed

    Cesaro, Simone; Marson, Piero; Gazzola, Maria Vittoria; De Silvestro, Giustina; Destro, Roberta; Pillon, Marta; Calore, Elisabetta; Messina, Chiara; Zanesco, Luigi

    2002-08-01

    Treatment of healthy donors with recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows the mobilization and peripheralization into circulating blood of an adequate number of CD34+ cells that can then be collected by leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow harvest and the risks related to general anesthesia. The main adverse effects of rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which are usually scored by the donors as moderate to severe, resolving within 2-3 days after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are sufficient to control the pain. Less than 5% of the donors experience non-cardiac chest pain, a local reaction at the injection site, insomnia, dizziness or a low-grade fever. Discontinuation of the PBSC procedure because of adverse effects of rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability can be hampered by the need, in 5-20% of cases, for an adequate venous access that requires insertion of a central or venous catheter. There are no absolute contraindications to the stimulation of healthy donors with rhG-CSF but the description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia, and gouty arthritis suggests that further precautionary restrictions are advisable when deciding eligibility for PBSC collection. The main advantages for patients receiving an allogeneic PBSC transplant are the faster hematologic and immunologic recovery and the potential for a greater efficacy in advanced disease by lowering the transplant-related mortality. One of the major concerns regarding the use of rhG-CSF in unrelated healthy donors is the uncertainty about its possible role in triggering malignancy, in particular myelodysplastic syndrome and acute myeloid leukemia. There are no studies with an adequate sample size and follow-up that can answer this question but two recent retrospective studies reported that in

  2. Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation.

    PubMed

    Casalegno-Garduño, Rosaely; Schmitt, Anita; Spitschak, Alf; Greiner, Jochen; Wang, Lei; Hilgendorf, Inken; Hirt, Carsten; Ho, Anthony D; Freund, Mathias; Schmitt, Michael

    2016-04-01

    Wilms' tumor gene 1 (WT1) is overexpressed in leukemia and WT1-derived CD8(+) T-cell epitopes for immunotherapies targeting WT1 have been defined. Here, we analyzed expression of WT1 in 226 peripheral blood and bone marrow samples from patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) before and after allogeneic stem cell transplantation (SCT). Transcripts were assessed by quantitative polymerase chain reaction, and WT1-specific CD8+ cytotoxic T cells (CTL) were monitored by tetramer staining and enzyme-linked immunospot (ELISPOT) assays. Reduction of WT1 levels correlated with a longer survival (p < 0.01). Increment of WT1 transcripts eventually resulted in relapse and subsequent death of the patients. In patients with longer survival and continuous complete remission (cCR) after SCT, higher and enduring frequencies of WT1-specific CTL than in patients developing a relapse were detected. These cells were effector T cells secreting interferon gamma and granzyme B. In summary, WT1 is a suitable marker for the detection of minimal residual disease after SCT or chemotherapy. A rising WT1 signal correlated with a dismal prognosis of the patients. WT1-specific CD8(+) T cells might contribute to the maintenance of a cCR. Targeting WT-1 by peptide/protein vaccination as well as adoptive transfer of genetically modified T cells are future options in the individualized therapy for AML/MDS patients. PMID:26519872

  3. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population

    PubMed Central

    Vasu, Sumithira; Leitman, Susan F.; Tisdale, John F.; Hsieh, Matthew M.; Childs, Richard W.; Barrett, A. John; Fowler, Daniel H.; Bishop, Michael R.; Kang, Elizabeth M.; Malech, Harry L.; Dunbar, Cynthia E.; Khuu, Hanh M.; Wesley, Robert; Yau, Yu Y.

    2008-01-01

    A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 μg/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34+ cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/μL, P < .001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34+ cell counts than donors who did not (94 vs 79 cells/μL, P < .001). In multivariate analysis, higher post–G-CSF CD34+ cell counts were most strongly associated with the total amount of G-CSF received, followed by the pre–G-CSF platelet count, pre–G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post–G-CSF CD34+ cell counts. PMID:18523146

  4. UNRELATED DONOR REDUCED INTENSITY ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR RELAPSED AND REFRACTORY HODGKIN LYMPHOMA

    PubMed Central

    Devetten, Marcel P.; Hari, Parameswaran N.; Carreras, Jeanette; Logan, Brent R.; van Besien, Koen; Bredeson, Christopher N.; Freytes, César O.; Peter Gale, Robert; Gibson, John; Giralt, Sergio A.; Goldstein, Steven C.; Gupta, Vikas; Marks, David I.; Maziarz, Richard T.; Vose, Julie M.; Lazarus, Hillard M.; Anderlini, Paolo

    2010-01-01

    Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin Lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% CI 10-21%) and 33% (95% CI 25-41%) respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and KPS < 90 were significant risk factors for TRM, PFS and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC vs NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute Graft-versus-Host Disease and relapse. PMID:19135949

  5. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation.

    PubMed

    Armand, Philippe; Kim, Haesook T; Logan, Brent R; Wang, Zhiwei; Alyea, Edwin P; Kalaycio, Matt E; Maziarz, Richard T; Antin, Joseph H; Soiffer, Robert J; Weisdorf, Daniel J; Rizzo, J Douglas; Horowitz, Mary M; Saber, Wael

    2014-06-01

    Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13,131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories. PMID:24744269

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

    PubMed Central

    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. PMID:21512651

  7. 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. PMID:21512651

  8. Favorable Outcomes in Patients with High Donor-Derived T Cell Count Following in vivo T Cell Depleted Reduced Intensity Allogeneic Stem Cell Transplantation

    PubMed Central

    Toor, Amir A.; Sabo, Roy T.; Chung, Harold M.; Roberts, Catherine; Manjili, Rose H.; Song, Shiyu; Williams, David C.; Edmiston, Wendy; Gatesman, Mandy L.; Edwards, Richard W.; Ferreira-Gonzalez, Andrea; Clark, William B.; Neale, Michael C.; McCarty, John M.; Manjili, Masoud H.

    2016-01-01

    Patients with hematological malignancies were conditioned using a rabbit anti-thymocyte globulin based reduced intensity conditioning regimen for allogeneic stem cell transplantation (SCT). Donor-derived CD3+ cell count (ddCD3), a product of CD3+ cell chimerism and absolute CD3+ cell count, when less than 110/μL, eight weeks post-transplant, predicted a high risk of sustained mixed chimerism and relapse. Alternatively, patients with a higher ddCD3 developed GVHD more frequently, and when partially chimeric, had higher rates of conversion to full donor chimerism upon withdrawal of immunosuppression. In conclusion, early data from a small cohort of patients indicates that ddCD3+ cell count at 8 weeks may be used to guide the decision-making process regarding withdrawal of immunosuppression and administration of donor lymphocyte infusion in partially T cell depleted reduced intensity regimens. PMID:22005648

  9. Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas.

    PubMed

    de Masson, Adèle; Beylot-Barry, Marie; Bouaziz, Jean-David; Peffault de Latour, Régis; Aubin, François; Garciaz, Sylvain; d'Incan, Michel; Dereure, Olivier; Dalle, Stéphane; Dompmartin, Anne; Suarez, Felipe; Battistella, Maxime; Vignon-Pennamen, Marie-Dominique; Rivet, Jacqueline; Adamski, Henri; Brice, Pauline; François, Sylvie; Lissandre, Séverine; Turlure, Pascal; Wierzbicka-Hainaut, Ewa; Brissot, Eolia; Dulery, Rémy; Servais, Sophie; Ravinet, Aurélie; Tabrizi, Reza; Ingen-Housz-Oro, Saskia; Joly, Pascal; Socié, Gérard; Bagot, Martine

    2014-03-01

    The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides. PMID:24213148

  10. 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. PMID:26259076

  11. 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

  12. 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

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

    PubMed

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

    2015-12-01

    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

  14. 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. PMID:24488049

  15. 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

  16. Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance.

    PubMed

    Mikulska, Malgorzata; Del Bono, Valerio; Raiola, Anna Maria; Bruno, Barbara; Gualandi, Francesca; Occhini, Domenico; di Grazia, Carmen; Frassoni, Francesco; Bacigalupo, Andrea; Viscoli, Claudio

    2009-01-01

    Blood stream infections (BSI) are a well-known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. The aim of this study was to analyze etiology and microbial resistance of BSI in patients undergoing allogeneic HSCT in a single center over a 4-year period (2004-2007). There were 168 episodes of BSI in 132 patients (median 10 days after HSCT) and 182 pathogens were isolated. Gram-positive bacteria (GPB) accounted for 57% of 182 isolates. Gram-negative rods (GNR) for 37% and fungi for 6%. All patients received routine fluoroquinolone prophylaxis. There was a significant decrease in GPB/GNR ratio over time, from 2.4 in 2004 to 1 in 2007 (P = .043). Among GPB, staphylococci decreased from 37 of 68 (64%) in 2004-2005 to 8 of 35 (23%) in 2006-2007 (P < .002). The Enterococcus faecalis/E. faecium ratio decreased from 4.5 in 2004 to 0.33 in 2007 (P = .006), whereas the total number of enterococcal strains per year did not change. The incidence of Escherichia coli among GNR increased from 3 of 15 (20%) in 2004 to 13 of 21 (62%) in 2007 (P = .003). Fluoroquinolone-resistance was common, both among GPB and GNR (81% and 74%, respectively). Mortality rate at 7 days after BSI was 11% (19 of 168), reaching 39% for Pseudomonas aeruginosa BSI (7 of 18). BSI remains a frequent and potentially life-threatening complication of allogeneic HSCT, the causative organism influencing 7- and 30-day mortality rate. BSI etiology may change rapidly, requiring implementation of new empirical-therapy schemes. PMID:19135942

  17. Impact of pretransplant serum ferritin level on risk of invasive mold infection after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Dadwal, Sanjeet S; Tegtmeier, Bernard; Liu, Xueli; Frankel, Paul; Ito, James; Forman, Stephen J; Pullarkat, Vinod

    2015-03-01

    Invasive mold infections (IMI) are life-threatening complications of allogeneic hematopoietic stem cell transplantation (HSCT) and are mostly caused by Aspergillus species and Mucorales. We examined whether elevated serum ferritin prior to HSCT was associated with increased risk of IMI after allogeneic HSCT. Elevated serum ferritin was defined as values ≥ 1000 ng/mL. Pretransplant ferritin levels were available for 477 transplants. Nine developed IMI at day 30 and 21 had IMI at day 100 for a cumulative incidence of 1.9% and 4.4%, respectively. Among the high ferritin group, eight of 220 transplant cases (3.6%) developed an IMI within 30 d after HSCT compared with one of 257 (0.4%) in the low ferritin group (P = 0.01). Fourteen of 220 (6.4%) and seven of 257 transplant cases (2.7%) in the high and low ferritin groups, respectively, had developed an IMI by day 100 after HSCT (P = 0.07). Nine of 53 (17%) patients with grades III and IV acute GVHD and iron overload experienced IMI, when compared to three of 37 (8.1%) with high-grade aGVHD, but no iron overload. Among patients without aGVHD, those with elevated ferritin had a 2.7% incidence of IMI compared with 0.9% for patients without elevated ferritin. There was a marginally significant difference in cumulative incidence function between high and low ferritin groups for IMI (P = 0.06). However, elevated serum ferritin (≥ 1000 ng/mL) was not a significant risk factor for IMI in a multivariate competing risk regression model after adjusting for aGVHD. PMID:25082161

  18. 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

  19. Adiponectin and resistin in acute and chronic graft-vs-host disease patients undergoing allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Robak, Oliver; Kuzmina, Zoya; Winkler, Andreas; Kalhs, Peter; Rabitsch, Werner; Greinix, Hildegard

    2016-01-01

    Aim To investigate the association of adiponectin and resistin levels in patients undergoing hematopoietic stem cell transplantation (HSCT) with the clinical outcome, including the occurrence of acute and chronic graft-vs-host disease (GVHD), non-relapse mortality, and overall survival. Methods We prospectively collected serum samples from 40 patients undergoing either autologous (n = 12; 10 male) or allogeneic (n = 28; 11 male) HSCT for up to 12 months post HSCT and determined adiponectin and resistin serum concentrations using enzyme-linked immunosorbent assay. Results There were no significant differences in adiponectin levels (18.5 vs 9.3 µg/mL, P = 0.071) and adiponectin/BMI ratio (0.82 vs 0.39, P = 0.068) between patients with acute GVHD grades 2-4 and autologous controls. However, resistin values were significantly lower in patients with acute GVHD grades 2-4 than in autologous controls (4.6 vs 7.3 ng/mL, P = 0.030). Adiponectin levels were higher in patients with chronic GVHD (n = 17) than in autologous controls (13.5 vs 7.6 µg/mL, P = 0.051), but the difference was not significant. Adiponectin/BMI ratio was significantly higher in patients with chronic GVHD than in autologous controls (0.59 vs 0.25, P = 0.006). Patients dying from relapse also had significantly lower adiponectin levels (8.2 µg/mL) and adiponectin/BMI ratio (0.3) on admission than surviving allogeneic (15.8 µg/mL, P = 0.030 and 0.7, P = 0.004) and surviving autologous patients (19.2 µg/mL, P = 0.031 and 0.7, P = 0.021). Conclusion Adiponectin and resistin levels were altered in patients with acute and chronic GVHD compared to autologous controls and were associated with overall survival and relapse mortality in patients undergoing allogeneic HSCT. PMID:27374827

  20. 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

  1. Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells

    PubMed Central

    Van Craenenbroeck, Amaryllis H.; Smits, Evelien L.J.; Anguille, Sébastien; Van de Velde, Ann; Stein, Barbara; Braeckman, Tessa; Van Camp, Kirsten; Nijs, Griet; Ieven, Margareta; Goossens, Herman; Berneman, Zwi N.; Van Tendeloo, Viggo F.I.; Verpooten, Gert A.; Van Damme, Pierre; Cools, Nathalie

    2015-01-01

    Background Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients. Methods The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA–loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval. Results De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial. Conclusion In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts. PMID:25050468

  2. [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

  3. 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

  4. Risk analysis of falls in patients undergoing allogeneic hematopoietic stem cell transplantation.

    PubMed

    Ueki, Satoko; Ikegame, Kazuhiro; Kozawa, Mariko; Miyamoto, Junko; Mori, Reiko; Ogawa, Hiroyasu

    2014-08-01

    To identify fall risks in patients undergoing hematopoietic stem cell transplantation (HSCT), the authors reviewed retrospective data on inpatients from April 2010 to March 2011. Among 77 HSCT patient records reviewed, the authors found that 35 patients had experienced at least one fall, including near-miss episodes (fallers). The main location of the falls was a corridor, and the main activity at the time of the fall was going to the toilet. To investigate fall risks along the HSCT time trajectory, the authors divided the time into pre- and post-engraftment periods and investigated the unique characteristics of each. PMID:25095291

  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. Reduction in incidence of invasive fungal infection in patients receiving allogeneic stem cell transplantation using combined diagnostic-driven approach and itraconazole oral solution.

    PubMed

    Tzadok, Roie; Shapira, Michael Y; Moses, Allon E; Or, Reuven; Block, Colin; Strahilevitz, Jacob

    2015-12-01

    Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic-driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non-significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic-driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non-statistically significant, number of IFI in our medical centre. PMID:26429354

  7. Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation.

    PubMed

    Machaczka, Maciej; Nahi, Hareth; Karbach, Holger; Klimkowska, Monika; Hägglund, Hans

    2012-06-01

    Acquired hemophagocytic lymphohistiocytosis (HLH) triggered by a known or still to be recognized malignancy is a life-threatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Malignancy-associated HLH (M-HLH) often impedes adequate treatment of malignancy and has the worst outcome compared with any other form of HLH. The incidence of M-HLH is unknown, and there are no published treatment recommendations addressed to this HLH form. Here, we report the case of a young woman with recurrent ALK1-positive anaplastic large T-cell lymphoma and M-HLH successfully treated with a modified HLH-94 protocol, allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI). More than 3 years after DLI, the patient is alive, in complete remission from her malignancy and HLH-free, although suffering from extensive chronic graft-versus-host disease. AlloSCT and, if needed, DLI performed to consolidate remission of malignancy and HLH may have a curative impact on both entities. We propose that when discussing possible treatment options for patients with M-HLH, alloSCT should be considered in eligible individuals. PMID:21533602

  8. Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation

    PubMed Central

    Curley, G. F.; Hamid, U. I.; Laffey, J. G.; Abbott, J.; McKenna, D. H.; Fang, X.; Matthay, M. A.; Lee, J. W.

    2014-01-01

    The lack of suitable donors for all solid-organ transplant programs is exacerbated in lung transplantation by the low utilization of potential donor lungs, due primarily to donor lung injury and dysfunction, including pulmonary edema. The current studies were designed to determine if intravenous clinical-grade human mesenchymal stem (stromal) cells (hMSCs) would be effective in restoring alveolar fluid clearance (AFC) in the human ex vivo lung perfusion model, using lungs that had been deemed unsuitable for transplantation and had been subjected to prolonged ischemic time. The human lungs were perfused with 5% albumin in a balanced electrolyte solution and oxygenated with continuous positive airway pressure. Baseline AFC was measured in the control lobe and if AFC was impaired (defined as <10%/h), the lungs received either hMSC (5 × 106 cells) added to the perfusate or perfusion only as a control. AFC was measured in a different lung lobe at 4 h. Intravenous hMSC restored AFC in the injured lungs to a normal level. In contrast, perfusion only did not increase AFC. This positive effect on AFC was reduced by intrabronchial administration of a neutralizing antibody to keratinocyte growth factor (KGF). Thus, intravenous allogeneic hMSCs are effective in restoring the capacity of the alveolar epithelium to remove alveolar fluid at a normal rate, suggesting that this therapy may be effective in enhancing the resolution of pulmonary edema in human lungs deemed clinically unsuitable for transplantation. PMID:24532289

  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. PMID:27311967

  10. Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia.

    PubMed

    Kudo, K; Muramatsu, H; Yoshida, N; Kobayashi, R; Yabe, H; Tabuchi, K; Kato, K; Koh, K; Takahashi, Y; Hashii, Y; Kawano, Y; Inoue, M; Cho, Y; Sakamaki, H; Kawa, K; Kato, K; Suzuki, R; Kojima, S

    2015-10-01

    The outcome of 55 children with severe aplastic anemia (SAA) who received a second hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed using the registration data of the Japanese Society for Hematopoietic Cell Transplantation. The 5-year overall survival (OS) and failure-free survival (FFS) after the second transplantation were 82.9% (95% confidence interval (CI), 69.7-90.8)) and 81.2% (95% CI, 67.8-89.4), respectively. FFS was significantly better when the interval between the first and second transplantation was >60 days (88.9%; 95% CI, 73.0-95.7) than when it was ⩽60 days (61.4%; 95% CI, 33.3-80.5; P=0.026). All 12 patients who were conditioned with regimens containing fludarabine and melphalan were alive with hematopoietic recovery. These findings justify the recommendation of a second HSCT for children with SAA who have experienced graft failure after first HSCT. PMID:26121106

  11. 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

  12. 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

  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. PMID:26301968

  14. Allogeneic hematopoietic stem cell transplantation for acquired aplastic anemia using cyclophosphamide and antithymocyte globulin: a single center experience.

    PubMed

    Ladeb, S; Abdelkefi, A; Torjman, L; Ben Neji, H; Lakhal, A; Kaabi, H; Ben Hamed, L; Ennigrou, S; Hmida, S; Ben Othman, T; Ben Abdeladhim, A

    2009-07-27

    Between February 1998 and October 2007, 97 (69 male, 28 female) patients with acquired aplastic anemia and a median age of 18 years (range, 2-39) received related allogeneic hematopoietic stem cell transplantation. Ninety-five patients received bone marrow grafts and two patients G-CSF primed peripheral blood stem cell transplantation. The donors were genotypically HLA-identical siblings in 94 cases, HLA-matched parents in 2 cases and a syngeneic twin in 1 case. Median time from diagnosis to transplantation was 2 months (range, 1-15). Conditioning regimen consisted of cyclophosphamide combined with antithymocyte globulin in all patients. For graft versus host disease (GVHD) prophylaxis, all patients received methotrexate and cyclosporine. Eighty-six patients showed evidence of hematopoietic engraftment. Eight patients died before engraftment. Rejection rate was 14.8% with three primary graft failures and eight secondary graft rejections occurring between 2 and 27 months post transplantation. Of the 11 rejecting patients, 3 died from infection and 8 proceeded to a second transplantation. Among the eight patients re-transplanted, seven are alive with successful second engraftments and one died from acute grade III GVHD. Acute GVHD occurred in 15.5% and extensive chronic GVHD in only 5.3% of patients. The 4-year overall probability of survival was 76.8%. Infection was the cause of 81.1% of deaths. The major factor affecting survival was onset of infection before transplantation. Major ABO donor-recipient incompatibility, disease severity and acute GVHD had also negative impact on survival. These results could be improved by reducing the time to transplant and by a more efficient supportive care policy.Bone Marrow Transplantation advance online publication, 27 July 2009; doi:10.1038/bmt.2009.175. PMID:19633695

  15. Bone marrow (stem cell) donation

    MedlinePlus

    Stem cell transplant; Allogeneic-donation ... There are two types of bone marrow donation: Autologous bone marrow transplant is when people donate their own bone marrow. "Auto" means self. Allogenic bone marrow transplant is when another person ...

  16. 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

  17. Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.

    PubMed

    Dalle, Jean-Hugues; Peffault de Latour, Régis

    2016-04-01

    Inherited bone marrow failure (IBMF) syndromes are a heterogeneous group of rare hematological disorders characterized by the impairment of hematopoiesis, which harbor specific clinical presentations and pathogenic mechanisms. Some of these syndromes may progress through clonal evolution, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Most prominent are failures of DNA repair such as Fanconi Anemia and much rarer failure of ribosomal apparatus, e.g., Diamond Blackfan Anemia or of telomere elongation such as dyskeratosis congenita. In these congenital disorders, hematopoietic stem cell transplantation (HSCT) is often a consideration. However, HSCT will not correct the underlying disease and possible co-existing extra-medullary (multi)-organ defects, but will improve BMF. Indications as well as transplantation characteristics are most of the time controversial in this setting because of the rarity of reported cases. The present paper proposes a short overview of current practices. PMID:26872907

  18. Control of relapsed or refractory acute myeloid leukemia by clofarabine in preparation for allogeneic stem cell transplant.

    PubMed

    Loeffler, Claudia; Kapp, Markus; Grigoleit, Goetz-Ulrich; Mielke, Stephan; Loeffler, Jürgen; Heuschmann, Peter U; Malzahn, Uwe; Hupp, Elke; Einsele, Hermann; Stuhler, Gernot

    2015-01-01

    Allogeneic stem cell transplant is indicated for patients with refractory or relapsed acute myeloid leukemia (AML). Since elimination of the leukemic load is thought to be a prerequisite for treatment success, we here investigate toxicity and anti-leukemic activity of a clofarabine-AraC salvage protocol preceding transplant. In this retrospective analysis, we observed induction of objective remissions in 86% of patients receiving clofarabine-AraC as compared to 83% with sequential high dose AraC/mitoxantrone (S-HAM) and 50% after mitoxantrone/topotecane/AraC (MTC) salvage strategies. In addition, clofarabine conferred anti-leukemic activity to some patients who failed initial MTC or S-HAM therapy. For overall and leukemia-free survival, we identified cytogenetically defined adverse risk markers but not response to therapy to be a strong predictor. In summary, the clofarabine-AraC salvage strategy combines pronounced anti-leukemic activity with an acceptable toxicity profile and allows the majority of patients with relapsed or refractory AML to proceed to allo-SCT, even in cytogenetically defined high risk situations. PMID:26014275

  19. Second Allogeneic Stem Cell Transplantation for Acute Leukemia Using a Chemotherapy-Only Cytoreduction with Clofarabine, Melphalan, and Thiotepa.

    PubMed

    Spitzer, Barbara; Perales, Miguel-Angel; Kernan, Nancy A; Prockop, Susan E; Zabor, Emily C; Webb, Nicholas; Castro-Malaspina, Hugo; Papadopoulos, Esperanza B; Young, James W; Scaradavou, Andromachi; Kobos, Rachel; Giralt, Sergio A; O'Reilly, Richard J; Boulad, Farid

    2016-08-01

    Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains one of the leading causes of mortality in patients with leukemia. Treatment options in this population remain limited, with concern for both increased toxicity and further relapse. We treated 18 patients with acute leukemia for marrow ± extramedullary relapse after a previous alloHSCT with a myeloablative cytoreductive regimen including clofarabine, melphalan, and thiotepa followed by a second or third transplantation from the same or a different donor. All patients were in remission at the time of the second or third transplantation. All evaluable patients engrafted. The most common toxicity was reversible transaminitis associated with clofarabine. Two patients died from transplantation-related causes. Seven patients relapsed after their second or third transplanation and died of disease. Nine of 18 patients are alive and disease free, with a 3-year 49% probability of overall survival (OS). Patients whose remission duration after initial alloHSCT was >6 months achieved superior outcomes (3-year OS, 74%, 95% confidence interval, 53% to 100%), compared with those relapsing within 6 months (0%) (P < .001). This new cytoreductive regimen has yielded promising results with acceptable toxicity for second or third transplantations in patients with high-risk acute leukemia who relapsed after a prior transplantation, using various graft and donor options. This approach merits further evaluation in collaborative group studies. PMID:27184623

  20. 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

  1. Nephrotic syndrome as a complication of chronic graft-versus-host disease after allogeneic haemopoietic stem cell transplantation.

    PubMed

    Wong, E; Lasica, M; He, S Z; Bajel, A; Roberts, A W; Mason, K D; Ritchie, D S; Szer, J

    2016-06-01

    Nephrotic syndrome (NS) is a rare complication following allogeneic haemopoietic stem cell transplantation (allo-HSCT), with limited current understanding of its pathogenesis. Here, we describe four cases of NS following allo-HSCT diagnosed at our institutions to identify key clinical and pathological features. In addition, a PubMed search was performed to identify existing reports that were pooled together with our cases for analysis. NS occurred as a late complication following allo-HSCT, with median onset 19.5 months after transplant (range: 3.9-84 months). The most common histopathology observed was membranous nephropathy; however, cases of minimal change disease have also been reported. There is a high incidence of prior extra-renal graft-versus-host disease (GvHD), with all four of our cases and 82% of published cases having prior GvHD. Glucocorticosteroids are the most common treatment, with variable degrees of response. Responses to immunosuppression with calcineurin inhibitors and rituximab have been described in steroid-refractory cases. PMID:27257151

  2. 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

  3. 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

  4. Pharmacogenetic aspects of drug metabolizing enzymes in busulfan based conditioning prior to allogenic hematopoietic stem cell transplantation in children.

    PubMed

    Huezo-Diaz, Patricia; Uppugunduri, Chakradhara Rao S; Tyagi, Anuj Kumar; Krajinovic, Maja; Ansari, Marc

    2014-03-01

    Allogenic hematopoietic stem cell transplantation (HSCT) is a well established but complex treatment option for malignant and non-malignant disorders in pediatric patients. Most commonly used myeloablative and non-myeloablative conditioning regimens in children comprise alkylating agents, such as busulfan (BU) and cyclophosphamide. Inter-individual variability in the pharmacokinetics of BU can result in altered conditioning of the patient and therefore lead to relapse or rejection due to under exposures, or occurrence of toxicities due to over exposures. With the introduction of the intravenous formulation of BU, this variability has been reduced but still cannot be fully predicted. Inter and intra-individual variability of BU kinetics is more common in children compared to adults and toxicity of BU based regimens is still a concern. It has been hypothesized that some of this variability in BU pharmacokinetics and treatment outcomes, especially the toxicity, might be predicted by genetic variants of enzymes involved in the metabolism of BU. This review intends to summarize the studies performed to date on the pharmacokinetics and pharmacogenetics of BU based conditioning, specifically in relation to children. PMID:24524663

  5. Late Toxicity of a Novel Allogeneic Stem Cell Transplant Using Single Fraction Total Body Irradiation for Hematologic Malignancies in Children

    PubMed Central

    Ngwube, Alexander I.; Shenoy, Shalini; Druley, Todd E.; Hayashi, Robert J.

    2015-01-01

    Single fraction total body irradiation (SFTBI) as part of a myeloablative preparative regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies was shown to have similar survival compared with fractionated total body irradiation (FTBI)-containing regimens, with less acute toxicity. The objective of this study was to determine long-term toxicity >2 years following SFTBI-based HSCT. Twenty-one patients were evaluated at a median follow-up of 6.8 years. Thyroid dysfunction was found in 21% of patients, 1 of whom (5.2%) was symptomatic; 23% had gonadal failure; 50% of patients with growth potential had linear growth disturbance; 27% had mild to moderate pulmonary disease; and 25% had cataracts. Intelligence quotient was stable. cGVHD was present in 28%, and 4 patients (19%) were on immune suppression 2 years posttransplant. Overall survival subsequent to 2 years posttransplant was 76% in this cohort of patients. No secondary malignancies were observed. In conclusion, the toxicities of SFTBI occurred at similar or reduced frequency compared with FTBI. SFTBI should be considered for patients who may benefit from a radiation-containing HSCT preparative regimen. PMID:25333837

  6. Scalded Skin of Rat Treated by Using Fibrin Glue Combined with Allogeneic Bone Marrow Mesenchymal Stem Cells

    PubMed Central

    Yang, Yadong; Li, Ying; Fang, Guojian; Zhang, Keji

    2014-01-01

    Background It is difficult to achieve satisfactory results with the traditional treatment of large-area skin defects and deep burns. Objective To test the treatment effect of an active dressing film made of a mixture of fibrin glue and bone marrow mesenchymal stem cells (BMSCs) for repairing burn wounds on the skin of rats. Methods Two scald wounds were made on the back of each rat. A total of 30 scald wounds were randomly divided into 3 groups, with 10 wounds in each group. In the experimental treatment group, the scald wounds were covered with the fibrin glue and BMSC mixture. The wounds of the experimental control group were covered with fibrin glue only. No intervention was administered to the blank control group. Thirty days after treatment, pathological sections were cut from the scalded local tissues of all rats from the 3 groups and observed with a microscope. Results The speed of scald wound healing in the experimental treatment group was faster than the other 2 groups. In the experimental treatment group, histopathological analysis revealed that the sebaceous glands showed obviously proliferous at the edge of the new tissue and gradually extended to the deep dermal layer of the new tissue. Conclusion BMSCs may have an active role in promoting skin tissue repair and generating skin appendages. Allogeneic BMSCs mixed with fibrin glue can contribute to the quick formation of a film-like gel over the scald wounds, which might be of significance for emergency treatment and skin-grafting operations. PMID:24966626

  7. β-d-Glucan Screening for Detection of Invasive Fungal Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Koltze, Antonia; Rath, Peter; Schöning, Stefan; Steinmann, Jörg; Wichelhaus, Thomas A.; Bader, Peter; Bochennek, Konrad

    2015-01-01

    While the assessment of β-d-glucan (BDG) levels in adults improves the early diagnosis of invasive fungal disease (IFD), data on BDG levels in children are limited. We therefore assessed in a prospective cohort study the value of serial BDG screening for early detection of IFD in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IFD was defined according to the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, with the necessary modification that BDG was not included as a microbiological criterion. For the analysis, a total of 702 serum samples were obtained in 34 pediatric HSCT recipients. Proven IFD occurred in two patients (fusariosis and Candida sepsis, respectively), and probable invasive aspergillosis was diagnosed in four patients. Analyses including different cutoff values for BDG levels and different definitions of the onset of IFD demonstrated that the BDG assay has a relatively high sensitivity and good negative predictive value, whereas the positive predictive value has major limitations (<30%). Receiver operating characteristic analyses suggested an optimal cutoff between 60 and 70 pg/ml for different definitions of the onset of IFD. Our data show that BDG screening in pediatric HSCT recipients has a low positive predictive value and is therefore of limited usefulness. PMID:26041896

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

    PubMed

    Anur, P; Friedman, D N; Sklar, C; Oeffinger, K; Castiel, M; Kearney, J; Singh, B; Prockop, S E; Kernan, N A; Scaradavou, A; Kobos, R; Curran, K; Ruggiero, J; Zakak, N; O'Reilly, R J; Boulad, F

    2016-07-01

    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 1 year post HSCT. Patients underwent either a 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 the 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, 4 (22%) developed hypothyroidism, 7 (39%) had insulin resistance and 5 (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

  9. Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.

    PubMed

    Sugio, Takeshi; Kato, Koji; Aoki, Takatoshi; Ohta, Takanori; Saito, Noriyuki; Yoshida, Shuro; Kawano, Ichiro; Henzan, Hideho; Kadowaki, Masanori; Takase, Ken; Muta, Tsuyoshi; Miyawaki, Kohta; Yamauchi, Takuji; Shima, Takahiro; Takashima, Shuichiro; Mori, Yasuo; Yoshimoto, Goichi; Kamezaki, Kenjiro; Takenaka, Katsuto; Iwasaki, Hiromi; Ogawa, Ryosuke; Ohno, Yuju; Eto, Tetsuya; Kamimura, Tomohiko; Miyamoto, Toshihiro; Akashi, Koichi

    2016-09-01

    Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development. PMID:27220263

  10. 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