Usage of porcine organs is a potential solution to the shortage of organs for transplantation. However it continues to be hindered by multiple immunologic barriers. Recent advances in genome engineering technology allow for the generation of porcine organ donors with multiplex gene edits. Here we evaluated survival of kidneys from triple xenoantigen knockout pigs that contain multiple human transgenes (Pig 2.0) in a life-sustaining non-human primate renal xenotransplant model. Cynomolgus macaques received kidneys from either GTKO.hCD55 pigs (n=2; reference group) or Pig 2.0 (n=8) followed by bilateral native nephrectomy. All Pig 2.0 donors were triple antigen knockout and expressed human complement, inflammation, and immune regulatory transgenes at different levels in three variations (Pig 2.5, 2.9, 2.10). Recipients were treated with anti-rhesus ATG and anti-CD20 mAb as induction, followed by weekly antiCD154 (hu5C8), daily mycophenolate mofetil (MMF) and, in the reference and 2.9 groups, methylprednisolone and short-term sirolimus. Animals were followed clinically with lab tests, serial ultrasound and protocol biopsies. Regardless of gene modifications, graft survival clustered into three patterns – rapid rejection within three weeks (n=4), delayed rejection at two months (n=3), and longer-term surviving where the animals were euthanized for nonrejection related complications (n=2). One animal remains on study at day 69 without evidence of rejection on his first protocol biopsy. The longest survivor (Pig 2.9) had no evidence of rejection on biopsy at day 237. MMF was discontinued on day 245 due to parvovirus-induced anemia. This intractable anemia led to sacrifice of the animal on day 265. Autopsy revealed TCMR, chronic AMR and TMA. Overall, graft rejection was associated with thrombotic microangiopathy (TMA), chronic antibody-mediated rejection (AMR) and T-cell Mediated Rejection (TCMR). Recipients were not screened for preformed anti-pig antibodies. Retrospective analysis showed longer-term survivors had lower IgM and IgG (MFI<500 and <2000, respectively) pretransplant antibody levels against donor endothelial cells than delayed (MFI >3000 and >8500) or rapid rejection groups (MFI >4500 and >8500). Two animals in the delayed rejection group revealed a small number of CD20+ B cells in autopsy samples on days 61 and 71, respectively. Genetic modification with depletion of xenoantigens and addition of human transgenes allowed kidney graft survival up to 265 days in the Pig 2.0 group. Lower pre-transplant donor specific antibody titers were generally associated with better post-transplant outcomes. 384.4

La Maladie de Behçet (MB) est une maladie auto-immune se présentant généralement par des ulcères buccaux et génitaux récidicants et une uvéite. Certains patients rares sont réfractaires aux traitements conventionnels. L’autogreffe de cellules souches hématopoïétiques (ACST) fait partie des traitements standards pour certaines maladies auto-immunes. Quelques patients atteints de MB ont été traités par ACST de manière compassionnelle en Europe. L’objectif de ce travail est d’évaluer le pronostic des patients atteints de MB traités par ACST au sein des centres de l’European Society for Blood and Bone Marrow Transplnatation (EBMT) Les critères d’éligibilités étaient: âge ≥ à 18 ans, traités par ACST pour une MB dans un centre EBMT qu’ils soient reportés dans le registre ou publiés dans la littérature. Les données ont été extraites des dossiers médicaux des patients ou des publications. Huit des neuf patients présents dans le registre ont été analysés ainsi que 2 autres patients provenant de la recherche bibliographique (1). Quatre patients étaient des femmes, l’âge médian au diagnostic de la MB était de 32 ans (27–51). Les patients avaient reçu en médiane 4 (2–11) lignes thérapeutiques (89 % des corticoïdes systémiques, 50 % du methotrexate, un anti-TNFα ou du cyclophosphamide). Tous les patients avaient une maladie active avant la mobilisation. le conditionnement était hétérogène. Le suivi médian était de 48 mois (6–240). Il n’y a pas de mortalité liée au traitement rapportée. Au dernier suivi, un patient n’a pas répondu, 3 patients ont rechuté sous la forme d’une pan-uvéite (n = 1), d’une aphtose (n = 2) d’arthralgie (n = 1). Deux patients étaient à nouveau sensibles à des traitements en échec avant la greffe (Azathioprine). Six patients sont restés en rémission complète. Aucune complication à long terme n’a été rapportée Le traitement par ACST dans la MB est faisable, sans toxicités majeures et permet de stabiliser des patients atteints de maladies mettant en jeu le pronostic vital.

Pulmonary graft versus host disease (GVHD), manifest as bronchiolitis obliterans, bronchiectasis and pulmonary fibrosis, is a serious complication of haematopoietic stem cell transplantation (HSCT) causing respiratory failure and death. There are limited therapeutic options for severe cases other than lung transplantation (LTx) but < 80 patients transplanted for GVHD have been reported worldwide. The optimum levels of immunosuppression required to prevent chronic lung allograft dysfunction (CLAD) yet maintain marrow function and avoid uncontrolled sepsis are unknown.

In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0–2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0–2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

All is not lost in accelerated phase/blast crisis and after tyrosine kinase inhibitors fail in chronic myeloid leukaemia: a retrospective study of allogeneic stem cell transplant outcomes in Australia and New Zealand

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

BACKGROUND:Survival after allogeneic haemopoietic stem cell transplantation (allo-HSCT) has improved because of advancements in allo-HSCT. Allo-HSCT has been performed in Australia since the late 1970s. However, there are few published data about health problems of allo-HSCT survivors in Australia.AIMS:Identify health issues in long-term survivors of allo-HSCT in an Australian centre to manage better and prevent long-term complications.METHODS:The health records of all patients of allo-HSCT in a single centre from January 2000 to December 2007 and survived beyond 2 years were assessed.RESULTS:Ninety-nine of the 200 allo-HSCT patients survived beyond 2 years, and the median time from allo-HSCT was 74 months. Twenty-eight per cent died at a median of 37 months after allo-HSCT because of relapsed malignancy (12%), stroke (1%), infection (3%), chronic graft versus host disease (9%), secondary malignancy (2%) and unknown cause (1%). Ninety-one per cent reported one or more chronic health conditions. Health issues were chronic graft versus host disease (70%); respiratory (66%), ophthalmic (40%), bone (33%), and renal (26%) problems; and malignancies (14% skin, 3% solid organ). Seventy-nine per cent resumed vocation at full or reduced capacity 2 years after allo-HSCT. Clinicians identified 40% with quality of life (QOL) issues, but survivors' self-reported QOL was comparable with the general Australian population.CONCLUSION:This study shows that allo-HSCT patients are living with high burdens of chronic diseases that warrant lifelong surveillance and engagement with healthcare. Structured, multi-disciplinary care as recommended by published guidelines for allo-HSCT survivors may reduce long-term effects and improve their outcomes.