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Oxford, United Kingdom

Medd P.,Oxford Radcliffe Hospitals NHS Trust | Littlewood S.,Oxford Radcliffe Hospitals NHS Trust | Danby R.,University of Oxford | Malladi R.,Oxford Radcliffe Hospitals NHS Trust | And 7 more authors.
Bone Marrow Transplantation | Year: 2011

Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P = 0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivationmore frequent in alemtuzumab recipientswas associated with paraproteinaemia (HR 7.52, P < 0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P = 0.048) and CMV reactivation (HR 5.74, P = 0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P = 0.04) and relapse increased (HR 2.38, P = 0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS. © 2011 Macmillan Publishers Limited All rights reserved.

Medd P.,Cancer and Haematology Center | Monk I.,Cancer and Haematology Center | Danby R.,University of Oxford | Malladi R.,Cancer and Haematology Center | And 8 more authors.
International Journal of Hematology | Year: 2011

We investigated the contributions of methotrexate (MTX) and ciclosporin (CsA) prophylaxis to acute/ chronic graft-versus-host disease (a/cGvHD) prevention following reduced-intensity conditioned allogeneic haematopoietic stem cell transplant (HSCT). Ninety-two fludarabine- melphalan sibling allo-SCT received CsA. Nine, 30 and 47 patients received no MTX, 2-3 doses and 4 doses, respectively. Cumulative CsA blood level to day 21 (CsA 21) was calculated. Grades II-IV aGvHD incidence was 37.2%. In multivariate analysis, MTX omission and increasing donor age significantly associated with aGvHD incidence whilst MTX reduction and CsA 21 did not. Median duration of first immunosuppressive therapy (IST) for aGvHD was 68 days; duration of first IST was significantly longer in older patients but was not associated with MTX or CsA 21. Extensive cGvHD incidence was 60.6% at 1 year. Reduction of MTX to 2-3 doses, but not MTX omission or CsA 21, was associated with greater incidence of cGvHD affecting ≥3 organs. Median IST duration was 22 months; neither MTX nor CsA 21 influenced this. IST duration was significantly greater in patients receiving a CD34 dose below median. Neither MTX nor CsA 21 altered survival or relapse outcomes. MTX influences GvHD following T-replete RIC sibling HSCT.

Moore C.,University of Cambridge | Sambrook J.,University of Cambridge | Walker M.,University of Cambridge | Tolkien Z.,University of Cambridge | And 10 more authors.
Trials | Year: 2014

Background: Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors.Methods/Design: INTERVAL is a randomised trial of whole blood donors enrolled from all 25 static centres of NHS Blood and Transplant. Recruitment of about 50,000 male and female donors started in June 2012 and was completed in June 2014. Men have been randomly assigned to standard 12-week versus 10-week versus 8-week inter-donation intervals, while women have been assigned to standard 16-week versus 14-week versus 12-week inter-donation intervals. Sex-specific comparisons will be made by intention-to-treat analysis of outcomes assessed after two years of intervention. The primary outcome is the number of blood donations made. A key secondary outcome is donor quality of life, assessed using the Short Form Health Survey. Additional secondary endpoints include the number of 'deferrals' due to low haemoglobin (and other factors), iron status, cognitive function, physical activity, and donor attitudes. A comprehensive health economic analysis will be undertaken.Discussion: The INTERVAL trial should yield novel information about the effect of inter-donation intervals on blood supply, acceptability, and donors' physical and mental well-being. The study will generate scientific evidence to help formulate blood collection policies in England and elsewhere. © 2014 Moore et al.

Medd P.G.,Oxford Radcliffe Hospitals NHS Trust | Clark N.,Oxford Radcliffe Hospitals NHS Trust | Leyden K.,Oxford Radcliffe Hospitals NHS Trust | Turner S.,Oxford Radcliffe Hospitals NHS Trust | And 7 more authors.
Cytometry Part B - Clinical Cytometry | Year: 2011

Background: Both chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are CD5/19 positive. The t(11;14) MCL translocation is identified by fluorescent in situ hybridization (FISH) and can distinguish the two disorders. We attempted to identify flow cytometric and other markers predictive of a positive FISH test. Methods: We examined 100 atypical CLL/MCL cases for demographic, hematological, and cytometric variables, 96 were FISH tested for t(11;14) and four were known MCL. Results: Twenty-two cases were confirmed as MCL. Multivariate analysis identified four variables associated with MCL: Thrombocytopenia (taken as Plt < 150 × 10 9/L), CD23 negative, CD20 strong, and CD38 positive, with these variables a four-point score was devised. By ROC analysis, the MCL score was superior in differentiating MCL to the Marsden CLL score (AUC 0.95 vs. 0.78). MCL score ≥2 showed sensitivity 1, specificity 0.66, positive predictive value (PPV) 0.49, and negative predictive value (NPV) 1 for MCL. The score was then prospectively validated on an independent cohort of 44 cases of atypical CLL/MCL. No MCL had a score <3. Validation PPV/NPV of score ≥3 were 0.5/1. Overall survival in MCL was shorter compared to t(11;14) negative patients (median 3.3 vs. 4.2 years, HR 2.2, 95% CI 0.87-5.5, P = 0.1). Conclusions: The score described can be used to identify cases of CD5/19 positive lymphoproliferative disorders likely to be t(11;14) positive MCL. © 2011 International Clinical Cytometry Society.

Zhang W.,Blood and Transplant Oxford Center | Nair S.,Blood and Transplant Oxford Center | Danby R.,Blood and Transplant Oxford Center | Danby R.,Cancer and Haematology Center | And 3 more authors.
Cytotherapy | Year: 2013

Background aims: Expansion of anti-CD25 bead-isolated human Tregs culture has paradoxically resulted in reduced suppressive activity, but the mechanism(s) responsible for these observations are poorly defined. Methods: Magnetic-bead isolated human CD25+ cells were expanded with anti-CD3/CD28 beads and high doses of rhIL-2. Detection of Fas and Fas ligand (Fas-L) expression, activation of Caspase 8, cell proliferation and cytokine production was evaluated by multi-color fluorescence-activated cell sorting analysis. The role of Fas-Fas-L-mediated cell death was dissected through the use of agonist or antagonist monoclonal antibodies directed at Fas and Fas-L. Results: Repeated expansion of bead-enriched CD4+CD25+ cells generated a cellular product with markedly reduced suppressive activity and with significantly increased CD8+ T cells and CD4+ T cells producing interferon-γ and/or interleukin-2. We showed that Fas-Fas-L-mediated apoptosis of CD4+FOXP3high cells and rapid cell-cycling of CD8+ Tcells were collectively responsible for the reduced proportion of CD4+FOXP3high cells in expanded cultures. The depletion of CD4+FOXP3high cells and activation of Caspase 8 in CD4+FOXP3high cells was attenuated by Fas antagonist antibody, ZB4, in short-term culture. However, the loss of CD4+FOXP3high cells during expansion was not prevented by either Fas or Fas-L antagonist antibodies. Conclusions: Taken together, the data show that Fas-Fas-L-mediated apoptosis may limit the expansion of anti-CD25 bead-isolated cells invitro. © 2013 International Society for Cellular Therapy.

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