References of "Biology of Blood & Marrow Transplantation"
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See detailEffect of post remission therapy prior to reduced intensity conditioning allogeneic transplantation for acute myeloid leukemia in first complete remission
Warlick, Erica; Paulson, Kristjan; Brazauskas, Ruta et al

in Biology of Blood & Marrow Transplantation (in press)

The impact of pre transplant (HCT) cytarabine consolidation therapy on post HCT outcomes has yet to be evaluated after reduced intensity or non-myeloablative conditioning. We analyzed 604 adults with ... [more ▼]

The impact of pre transplant (HCT) cytarabine consolidation therapy on post HCT outcomes has yet to be evaluated after reduced intensity or non-myeloablative conditioning. We analyzed 604 adults with acute myeloid leukemia (AML) in first complete remission (CR1) reported to the CIBMTR who received a RIC or NMA HCT from an HLA-identical sibling, HLA-matched unrelated donor (URD), or umbilical cord blood (UCB) donor in 2000-2010. We compared transplant outcomes based on exposure to cytarabine post remission consolidation. Three year survival rates were 36% (29-43%, 95% CI) in the no consolidation arm and 42% (37-47%, 95% CI) in the cytarabine consolidation arm (p=0.16). Disease free survival was 34% (27-41%, 95% CI) and 41% (35-46%, 95% CI) (p=0.15), respectively. Three year cumulative incidences of relapse were 37% (30-44%, 95% CI) and 38% (33-43%, 95% CI), respectively (p=0.80). Multivariate regression confirmed no effect of consolidation on relapse, DFS and survival. Prior to RIC/NMA HCT, these data suggest pre-HCT consolidation cytarabine does not significantly alter outcomes and support prompt transition to transplant as soon as morphologic CR1 is attained. If HCT is delayed while identifying a donor, our data suggest that consolidation does not increase transplant TRM and is reasonable if required. [less ▲]

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See detailLong term Immune Reconstitution and infection burden after Mismatched Hematopoietic Stem Cell Transplantation
SERVAIS, Sophie ULg; Lengline, Etienne; Porcher, Raphael et al

in Biology of Blood & Marrow Transplantation (in press)

Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long lasting immune deficiency ... [more ▼]

Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long lasting immune deficiency. Sixty-six patients who underwent a first transplantation from either UCB or 9/10 MMUD (n= 36) and who survived beyond 3 months were evaluated. Immune reconstitution was prospectively assessed at sequential time points after transplantation. NK, B, CD4+ and CD8+T cells and their subsets as well as regulatory T cells (Treg) were studied. Detailed analyses on infections occurring after 3 months were also assessed. The 18-month cumulative incidences of infection-related death were 8 and 3%, and of infections were 72 and 57% after MMUD and UCB transplantation, respectively. Rates of infection per 12 patient-month were roughly 2 overall (1 for bacterial, 0.9 for viral and 0.3 for fungal infections). Memory, naïve CD4+ and CD8+T cells, naïve B cells and Treg cells reconstitution between the 2 sources was roughly similar. Absolute CD4+T cells hardly reached 500 per μL by one year posttransplantation and most B cells were of naïve phenotype. Correlations between immune reconstitution and infection were then performed by multivariate analyses. Low CD4+ and high CD8+T cells absolute counts at 3 months were linked to increased risks of overall and viral (but not bacterial) infections. When assessing for the naïve/memory phenotypes at 3 months among the CD4+ T cell compartment, higher percentages of memory subsets were protective against late infections: central memory CD4+T cells protected against overall and bacterial infections; late effector memory CD4+T cells protected against overall, bacterial and viral infections. At the opposite, high percentage of effector- and late effector-memory subsets at 3 months among the CD8+ T cell compartment predicted higher risks for viral infections. Patients transplanted from alternative donors represent a population with very high risk of infection. Detailed phenotypic analysis of immune reconstitution may help to evaluate infection risk and to adjust infection prophylaxis. [less ▲]

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See detailAntithymocyte globulin before allogeneic stem cell transplantation for progressive myelodysplastic syndrome : a study from the French Society of Bone Marrow Transplantation and Cellular Therapy
Duléry, Rémy; Mohty, Mohamad; Duhamel, Alain et al

in Biology of Blood & Marrow Transplantation (2014), 20

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 ... [more ▼]

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 consecutive patients who underwent allo-SCT for progressive MDS between October 1999 and December 2009, 93 received ATG (ATG group) at the median dose of 5 mg/kg, whereas 149 patients did not (no-ATG group). Donors were sibling (n ¼ 153) or HLA-matched unrelated (n ¼ 89). Patients received blood (n ¼ 90) or marrow (n ¼ 152) grafts after either myeloablative (n ¼ 109) or reduced-intensity (n ¼ 133) conditioning. Three-year overall and event-free survival, nonrelapse mortality, relapse, and chronic graft-versus-host disease (GVHD) development were not significantly different between the 2 groups. In contrast, acute grade II to IV GVHD occurred more often in the no-ATG group (55% of the patients) than in the ATG group (27%, P < .0001). Similar results were observed with acute grade III to IV GVHD (28% and 14% in the no-ATG group and ATG group, respectively; P ¼ .009). In multivariate analysis, after adjustment with propensity score, the absence of ATG was the strongest parameter associated with an increased risk of acute grade II to IV GVHD (hazard ratio, 2.13; 95% confidence interval, 1.35 to 3.37; P ¼.001]. ATG had no impact on overall and event-free survival or cumulative incidence of the relapse. In conclusion, the addition of ATG to allo-SCT conditioning did not increase the incidence of relapse of patients with progressive MDS. The incidence of acute GVHD was decreased without compromising outcomes. [less ▲]

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See detailEffect of HLA-matching recipients to donor non-inherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy
Rocha, V; Spellman, S; Zhang, MJ et al

in Biology of Blood & Marrow Transplantation (2012)

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See detailMesenchymal stromal cells : a new tool against graft-versus-host disease ?
Baron, Frédéric ULg; Storb, Rainer

in Biology of Blood & Marrow Transplantation (2012), 18(6), 822-840

Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti ... [more ▼]

Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti-inflammatory properties that prompted their clinical use as prevention and/or treatment for severe graft-versus-host disease (GVHD). Although a number of phase I-II studies have suggested that MSCs infusion was safe and might be effective for preventing or treating acute GVHD, definitive proof for their efficacy remains lacking thus far. Multicenter randomized studies are ongoing to more precisely assess the impact of MSCs infusion on GVHD prevention/treatment, whereas further research is performed in vitro and in animal models with the aims of determining the best way to expand MSCs ex vivo as well as the most efficient dose and schedule of MSCs administration. After introducing GVHD, MSC biology, and results of MSCs infusion in animal models of allogeneic hematopoietic cell transplantation, this article reviews the results of the first clinical trials investigating the use of MSCs infusion as prevention or treatment of GVHD. [less ▲]

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See detailCotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning.
Baron, Frédéric ULg; Lechanteur, Chantal ULg; Willems, Evelyne ULg et al

in Biology of Blood & Marrow Transplantation (2010), 16(6), 838-47

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD ... [more ▼]

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD) after myeloablative allogeneic HCT. This prompted us to investigate in a pilot study whether MSC infusion before HCT could allow nonmyeloablative (NMA) HCT (a transplant strategy based nearly exclusively on graft-versus-tumor effects for tumor eradication) from HLA-mismatched donors to be performed safely. Twenty patients with hematologic malignancies were given MSCs from third party unrelated donors 30-120 minutes before peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors, after conditioning with 2 Gy total body irradiation (TBI) and fludarabine. The primary endpoint was safety, defined as a 100-day incidence of nonrelapse mortality (NRM) <35%. One patient had primary graft rejection, whereas the remaining 19 patients had sustained engraftment. The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 35%, whereas 65% of the patients experienced moderate/severe chronic GVHD (cGVHD). One-year NRM (10%), relapse (30%), overall survival (OS) (80%) and progression-free survival (PFS) (60%), and 1-year incidence of death from GVHD or infection with GVHD (10%) were encouraging. These figures compare favorably with those observed in a historic group of 16 patients given HLA-mismatched PBSCs (but no MSCs) after NMA conditioning, which had a 1-year incidence of NRM of 37% (P = .02), a 1-year incidence of relapse of 25% (NS), a 1-year OS and PFS of 44% (P = .02), and 38% (P = .1), respectively, and a 1-year rate of death from GVHD or infection with GVHD of 31% (P = .04). In conclusion, our data suggest that HLA-mismatched NMA HCT with MSC coinfusion appeared to be safe. [less ▲]

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See detailWhat Is The Role For Regulatory T-Cells After Nonmyeloablative Conditioning?
Humblet-Baron, S.; CASTERMANS, Emilie ULg; Vanbellinghen, J.-F. et al

in Biology of Blood & Marrow Transplantation (2009, February), 15(2), 122-123

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See detailWhat is the role for donor natural killer cells after nonmyeloablative conditioning?
Baron, Frédéric ULg; Petersdorf, Effie W; Gooley, Ted et al

in Biology of Blood & Marrow Transplantation (2009), 15(5), 580-8

We investigated the impacts of the tempo of early (days 14, 28, and 42) donor T cell and natural killer (NK) cell engraftment, missing recipient killer cell immunoglobulin-like receptor (KIR) ligands, and ... [more ▼]

We investigated the impacts of the tempo of early (days 14, 28, and 42) donor T cell and natural killer (NK) cell engraftment, missing recipient killer cell immunoglobulin-like receptor (KIR) ligands, and numbers of donor inhibitory and activating KIR genes on hematopoietic cell transplantation (HCT) outcomes in 282 patients with hematologic malignancies given nonmyeloablative conditioning. Modeling chimerism levels as a continuous linear variable, we found that high early donor T cell chimerism was significantly associated with acute graft-versus-host disease (aGVHD) (P = .01), whereas high donor NK cell chimerism levels had no such association (P = .38). Conversely, high donor NK cell chimerism levels were significantly associated with low relapse risk (P = .0009), whereas no significant association was seen with high donor T cell chimerism (P = .10). The qualitative associations between donor T cell and NK cell chimerism levels and GVHD and relapse did not change after adjustment for the presence of recipient KIR ligands or numbers of donor inhibitory or activating KIR genes. Our data indicate that prompt engraftment of donor NK cells correlated with lessened risks of relapse, but not with GVHD, whereas the converse was true for T cells. [less ▲]

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See detailWhat is the Role for Regulatory T-Cells after Nonmyeloablative conditioning
Humblet-Baron, S.; CASTERMANS, Emilie ULg; Vanbellighen, J.-F. et al

in Biology of Blood & Marrow Transplantation (2008, February), 14(2), 136-137

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See detailExtended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning
Baron, Frédéric ULg; Sandmaier, Brenda M.; Storer, Barry E. et al

in Biology of Blood & Marrow Transplantation (2007), 13(9), 1041-1048

We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after ... [more ▼]

We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after nonmycloablative conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day + 40 with taper through day + 96) and cyclosporine (CSP; given from day -3 to day + 100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of NMF, given at full dosing until day + 150 and then tapered through day + 180, and a shortened course of CSP, through day + 80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade ll-1V aGVHD and 45% extensive cGVHD (P =.03, and P =.43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively (P =.89, P =.02, and P =.08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given nonmyeloablative conditioning. (c) 2007 American Society for Blood and Marrow Transplantation [less ▲]

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See detailUnrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning
Baron, Frédéric ULg; Storer, Barry; Maris, Michael B. et al

in Biology of Blood & Marrow Transplantation (2006), 12(11), 1176-1187

The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We ... [more ▼]

The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We therefore investigated factors affecting immune recovery in 94 patients given HCT from MRDs (n = 51) and URDs (n = 43) after 2-Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. CD4 T cells counts remained below normal values during the first year after HCT in both patient groups. This included abnormally low counts each of naive CD4 T cells and memory CD4 T cells. Conversely, CD8 T cell counts reached the 10th percentile of normal 6 months after HCT in MRD and URD recipients. On day 30 after HCT, URD recipients had lower counts of B cells (P = .02), naive CD4 T cells (P = .04), memory CD4 T cells (P = .005), memory CD8 T cells (P = .005), and CMV-specific T helper cells (P = .007) than had MRD recipients. This delay in CMV-specific immune reconstitution translated into increased frequency of CMV antigenemia among URD recipients during the first 100 days after HCT. Older donor age was associated with low counts of naive CD4 T cells on days 180-365 after HCT (P = .003). Further, low numbers of T cells and CD34(+) cells in the graft and development of acute graft-versus-host disease were associated with impaired immune recovery of naive CD4 T cells and B cells. In summary, immunologic recovery was poor the first year after nonmyeloablative conditioning and was delayed among URD recipients in comparison with MRD recipients. Other factors significantly associated with delayed immune recovery were advanced donor age, low numbers of CD34 and T cells in the graft, and development of graft-versus-host disease. (C) 2006 American Society for Blood and Marrow Transplantation. [less ▲]

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See detailWhat role is there for antithymocyte globulin in allogeneic nonmyeloablative canine hematopoietic cell transplantation?
Diaconescu, Razvan; Little, Marie-Terese; Leisenring, Wendy et al

in Biology of Blood & Marrow Transplantation (2005), 11(5), 335-44

We investigated whether pretransplantation immunosuppression with canine-specific rabbit antithymocyte globulin (ATG), combined with a suboptimal dose of 1 Gy of total body irradiation (TBI), would permit ... [more ▼]

We investigated whether pretransplantation immunosuppression with canine-specific rabbit antithymocyte globulin (ATG), combined with a suboptimal dose of 1 Gy of total body irradiation (TBI), would permit engraftment of canine dog leukocyte antigen-identical marrow. Cumulative ATG doses of 2 to 5 mg/kg produced a T-cell depletion of 1 log in the peripheral blood and 50% in the lymph nodes. Serum levels of ATG peaked on days 4 to 6 after initiation of therapy and became undetectable by day 13 as a result of canine antibody responses to ATG. ATG prolonged allogeneic skin graft survival to 14 days (n = 5), compared with 8 days in control dogs (P = .0003). Five dogs were given marrow transplants after ATG (3.5-5 mg/kg) and 1 Gy of TBI. Posttransplantation immunosuppression consisted of mycophenolate mofetil and cyclosporine. All dogs showed initial engraftment, with maximum donor chimerism levels of 25%. However, only 1 dog achieved sustained engraftment, and 4 rejected their grafts. The duration of engraftment ranged from 8 to > or = 36 weeks (median, 11 weeks), and this is comparable to that in 6 historical controls not given ATG (range, 3-12 weeks; median, 10 weeks; P = .20). The total nucleated cell doses in the marrow grafts had the highest correlation coefficient with the duration of engraftment: 0.82 (P = .09). We concluded that administering ATG before an otherwise suboptimal conditioning dose of 1 Gy of TBI failed to secure uniform stable hematopoietic engraftment. [less ▲]

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See detailAssessing donor chimerism level among CD3 T, CD4 T, CD8 T, and NK cells predicts subsequent graft rejection, GVHD, and relapse after allogeneic HCT with nonmyeloablative conditioning
Baron, Frédéric ULg; Storb, R.; Gooley, T. et al

in Biology of Blood & Marrow Transplantation (2005), 11(2), 11

We previously showed that low levels of day-14 CD3 T and NK (CD56) cells donor chimerism predicted graft rejection, whereas high levels of day-28 CD3 T-cell donor chimerism predicted acute graft-versus ... [more ▼]

We previously showed that low levels of day-14 CD3 T and NK (CD56) cells donor chimerism predicted graft rejection, whereas high levels of day-28 CD3 T-cell donor chimerism predicted acute graft-versus-host disease (GVHD) after HCT with nonmyeloablative conditioning. Here we investigate whether assessing chimerism levels among CD4 T cells and CD8 T cells, and also the absolute number of lymphocyte subsets of donor and host origins, would lend greater precision to our initial observations. We analyzed data from 157 patients receiving HCT after conditioning with 2 Gy TBI +/− fludarabine as treatment for AML (n= 22), ALL (n= 4), CML (n= 13), CLL (n= 19), MDS (n= 26), MM (n= 24), NHL (n= 30), HD (n= 14), RCC (n= 4), and WASP deficiency (n= 1). Postgrafting immunosuppression included MMF and CSP. A total of 97 patients received grafts from HLA-identical siblings, and 60 patients received grafts from HLA-matched unrelated donors. Lymphocyte subsets were isolated from peripheral blood by flow cytometry on days 14, 28, and 42. The proportion of cells of donor origin (chimerism levels) were assessed by VNTR-PCR and quantified by phosphor imaging. Eighteen patients (11%) had graft rejection. Day-14 donor chimerism levels< 50% among CD3 T (P =.0007), CD4 T (P =.03), and NK cells (P =.003) but not CD8 T cells predicted graft rejection. High absolute numbers of CD3 T (P =.002) and NK cells (P= .002) of host origin on day 14 were each associated with increased risks of graft rejection when treated as continuous linear variables. Grades 2, 3, and 4 acute GVHD were seen in 40%, 9%, and 5% of patients, respectively. High donor chimerism levels on day 14 among CD3 T (P= .02), CD4 T (P =.03), and CD8 T cells (P =.02) but not NK cells were each associated with increased risks of grades 2–4 acute GVHD. High absolute numbers of CD4 T (P =.04) and CD8 T cells (P =.04) of donor origin on days 14–42 were each associated with increased risks of grade 2–4 acute GVHD when treated as continuous linear variables, whereas high donor CD3 T (P= .002), CD8 T (P= .006), and NK cell (P= .002) chimerism levels from days 14–42 were associated with decreased risks of relapse. No statistically significant correlations between absolute numbers of donor cells and risks of relapse were found. These data suggest that assessing CD3, CD4, CD8, and NK cell donor chimerism levels and determining absolute numbers of CD3 and NK cells of host and donor origins are useful for predicting HCT outcomes after nonmyeloablative conditioning. [less ▲]

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See detailPreemptive cellular immunotherapy after T-cell-depleted allogeneic hematopoietic stem cell transplantation.
Baron, Frédéric ULg; Beguin, Yves ULg

in Biology of Blood & Marrow Transplantation (2002), 8(7), 351-9

GVHD is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is due to donor lymphocytes that are cotransplanted with donor stem cells. These donor ... [more ▼]

GVHD is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is due to donor lymphocytes that are cotransplanted with donor stem cells. These donor lymphocytes are primed by histocompatibility differences between donors and recipients and activated by a cytokine storm caused by the conditioning regimen. The most efficient method for prevention of GVHD consists of T-cell depletion (TCD) of the graft. However, TCD usually leads to an increased risk of leukemia relapse because of the loss of the graft-versus-leukemia (GVL) effect. Several groups have studied the feasibility of preemptive donor lymphocyte infusion (DLI) to lessen the impact of TCD on leukemia relapse. Preemptive DLI is given several weeks to months after the transplantation, ie, after the cytokine storm and after the patient has recovered from conditioning-regimen-related toxicities. After briefly discussing various techniques of TCD of the graft and the efficacy of DLI, this article reviews the first clinical studies evaluating a strategy of TCD of the graft followed by preemptive DLI. [less ▲]

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