What Is The Role For Regulatory T-Cells After Nonmyeloablative Conditioning?
; CASTERMANS, Emilie ; et al
in Biology of Blood & Marrow Transplantation (2009, February), 15(2), 122-123Detailed reference viewed: 11 (3 ULg)
Immunobiology of reduced intensity conditioning in hematopoietic stem cell transplantation
Baron, Frédéric ;
in Hematology education : the education program for the annual congress of the European Hematology Association (2009)Detailed reference viewed: 10 (0 ULg)
A prospective randomized multicenter trial of darbepoetin-alfa and I.V. iron administration after autologous hematopoietic stem cell transplantation.
Beguin, Yves ; ; DE PRIJCK, Bernard et al
We conducted a multicenter prospective randomized study analyzing the impact of darbepoetin alfa (DA) with or mithout i.v. iron on erythroid recovery after autologous HCT.Detailed reference viewed: 20 (4 ULg)
Thymic Recovery After Allogeneic Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning Might Be Limited to Patients Younger Than 60 Years of Age.
; Hannon, Muriel ; et al
in Blood (2009), 114(22), 1149Detailed reference viewed: 9 (1 ULg)
Reconstitution du système immunitaire après allogreffe de cellules souches hématopoïétiques
Castermans, Emilie ; Hannon, Muriel ; Drion, Pierre et al
in Revue Médicale de Liège (2009), 64(S1), 2-8
Allogeneic hematopoietic stem cell transplantation (alloHCT) is frequently used as treatment for patients with hematological malignancies. Its efficacy depends in part on the destruction of recipient ... [more ▼]
Allogeneic hematopoietic stem cell transplantation (alloHCT) is frequently used as treatment for patients with hematological malignancies. Its efficacy depends in part on the destruction of recipient tumors cells by donor immune cells contained in the graft (graft-versus-tumor effects), underlying the interest of stydying donor immune recovery after alloHCT. Further, donor immune cells play an important role in the prevention and treatment of infections after allHCT, and are the cause of graft-versus-host disease (GVHD). This article reviews the mechanisms of immune recovery after allogeneic hematopoietic cell transplantation (alloHCT), as well as techniques currently used to monitor immune function following allHCT. [less ▲]Detailed reference viewed: 116 (29 ULg)
Co-transplantation of mesenchymal stem cells might mitigate acute GvHD without abrogating graftversus- tumour alloreactivity after allogeneic transplantation with non-myeloablative conditioning
Baron, Frédéric ; WILLEMS, Evelyne ; LECHANTEUR, Chantal et al
Background: Results of nonmyeloablative HCT in pts with HLA-mismatched donors have been disappointing due to high incidence of graft rejection and severe acute GVHD. Recent studies have suggested that ... [more ▼]
Background: Results of nonmyeloablative HCT in pts with HLA-mismatched donors have been disappointing due to high incidence of graft rejection and severe acute GVHD. Recent studies have suggested that infusion of mesenchymal stem cells (MSC) the day of HCT might promote engraftment and prevent acute GVHD after myeloablative allogeneic HCT. However, some studies suggested that MSC co-infusion might abrogate graft-versus-host alloreactivity and graft-versus-tumor effects. This prompted us to investigate whether MSC infusion a few hours before HCT could allow nonmyeloablative HCT from HLA-mismatched donors to be performed safely (i.e. with a 100-day incidence of nonrelapse mortality < 35%). Methods: 20 patients with hematological malignancies were given MSC (1-2 x 10E6 cells/kg) from third party donors a few hours before PBSC from HLA-mismatched unrelated donors, after conditioning with 2 Gy TBI and fl udarabine 90 mg/m. Postgrafting immunosuppression included tacrolimus (day -3 to +180; tapered by day +365) and mycophenolate mofetil (tid days 0 to +42). HLA-compatibility was assessed at the HLA-A, -B, -C, -DRBI and DQBI loci: 13 pairs were mismatched for at least one HLA class I antigen (including 4 pairs who were also mismatched for 1 HLA-class II antigens (n=3) or 1 HLA-class I allele (n=1)), 1 pair was mismatched for 2 HLA class II alleles, while 6 pairs were mismatched for a single HLA class I (n=3) or HLA class II (n=3) alleles. Results: Median follow-up for surviving patients was 288 (range, 76-571) days. One patient with secondary AML had primary graft rejection, while the remaining 19 patients had sustained engraftment. Median donor T-cell chimerism levels on days 28, 100, 180 and 365 after HCT were 90%, 98%, 96%, and 98%, respectively. Grade II, III and IV acute GVHD were seen in 5, 2 and 1 patients, respectively, while 7 experienced NIH moderate/severe chronic GVHD. Three of 7 patients with measurable disease at transplantation achieved complete remission on days 41, 104 and 353 after HCT. Two patients died of nonrelapse causes on days 74 and 114 after HCT, while 3 died of disease progression. Projected 1-yr overall and progressionfree survivals were 77% and 61%, respectively. Conclusions: HLA-mismatched nonmyeloablative HCT with MSC co-infusion appeared to be safe, with MSC co-infusion possibly mitigating graft-versus-host alloreactivity without abrogating graft-versus-tumor effects. Survival is encouraging. [less ▲]Detailed reference viewed: 15 (3 ULg)
What is the role for donor natural killer cells after nonmyeloablative conditioning?
Baron, Frédéric ; ; 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 ▲]Detailed reference viewed: 86 (4 ULg)
Non-myeloablative transplantation with CD8-depleted or unmanipulated peripheral blood stem cells: a phase II randomized trial.
Willems, Evelyne ; Baron, Frédéric ; Baudoux, Etienne et al
in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2009), 23(3), 608-10Detailed reference viewed: 74 (36 ULg)
Cancers secondaires après allogreffe de cellules souches hématopoïétiques
Hafraoui, Kaoutar ; Beguin, Yves ; Baron, Frédéric
in Revue Médicale de Liège (2009), 64(10), 496-499
This article reviews the incidence, risk factors and prevention of secondary malignancies after allogeneic hematopoietic cell transplantation.Detailed reference viewed: 103 (10 ULg)
Impact of growth hormone (GH) deficiency and GH replacement upon thymus function in adult patients.
Morrhaye, Gabriel ; ; Legros, Jean-Jacques et al
in PLoS ONE (2009), 4(5), 5668
BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 ... [more ▼]
BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. CONCLUSIONS: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. TRIAL REGISTRATION: ClinicalTrials.gov NTC00601419. [less ▲]Detailed reference viewed: 153 (29 ULg)
Toxoplasmore cérébrale compliquant une mini-allogreffe de cellules souches hématopoïétiques du sang périphérique
; ; Willems, Evelyne et al
in Revue Médicale de Liège (2009), 64(7-8), 366-369
We report the occurrence of a cerebral toxoplasmosis 52 days after a non-myeloablative allogeneic stem cell transplantation as treatment for acute myeloid leukemia.Detailed reference viewed: 85 (7 ULg)
What is the Role for Regulatory T-Cells after Nonmyeloablative conditioning
; CASTERMANS, Emilie ; et al
in Biology of Blood & Marrow Transplantation (2008, February), 14(2), 136-137Detailed reference viewed: 12 (2 ULg)
Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning
Baron, Frédéric ; ;
in Innovative Leukemia and Lymphoma Therapy (2008)Detailed reference viewed: 4 (1 ULg)
Intensified postgrafting immunosuppression failed to assure long-term engraftment of dog leukocyte antigen-identical canine marrow grafts after 1 gray total body irradiation.
; ; et al
in Transplantation (2008), 85(7), 1023-9
BACKGROUND: Late graft rejection after conditioning with 1 Gy of total body irradiation (TBI) was consistently seen in historical dogs given two postgrafting immunosuppressive drugs. METHODS: Here, 16 ... [more ▼]
BACKGROUND: Late graft rejection after conditioning with 1 Gy of total body irradiation (TBI) was consistently seen in historical dogs given two postgrafting immunosuppressive drugs. METHODS: Here, 16 dogs were given four different three-drug combinations of cyclosporine, mycophenolate mofetil, sirolimus, or methotrexate after 1 Gy TBI and dog leukocyte antigen-identical marrow grafts. In addition, we assessed the effects of TBI doses of 0.5, 1.0, 2.0, or 3.0 Gy, respectively, on immune functions in six dogs not given marrow grafts. RESULTS: All dogs showed initial engraftment, 13 rejected, and three had sustained grafts beyond 26 weeks. The dogs with durable grafts had received greater median numbers of nucleated marrow cells compared with the 13 dogs that rejected their grafts (6.14 vs. 3.6 x 10(8) per kg; P=0.03). In a Cox proportional hazard model, which included data from 16 historical dogs, each increase in transplanted marrow cell numbers by 1 x 10(8) per kg decreased the hazard ratio of rejection by 0.5. Decreasing percents of remaining CD3, CD4, and CD8 cells in peripheral blood and lymph nodes were observed with increasing TBI doses. Further, greater suppressions of B-cell- and T-cell-dependent production of IgM and IgG antibodies in response to sheep red blood cell injections were observed after 2 Gy compared with 1 Gy TBI. CONCLUSION: Overall, triple postgrafting immunosuppression after 1 Gy TBI was well tolerated but failed to prevent graft rejection in this model. In vivo radiation studies have shown higher numbers of remaining host lymphocytes and better T-cell-dependent antibody production after 1 Gy compared with 2 Gy TBI. [less ▲]Detailed reference viewed: 94 (0 ULg)
Evidence for neo-generation of T cells by the thymus after non-myeloablative conditioning.
Castermans, Emilie ; Baron, Frédéric ; Willems, Evelyne et al
in Haematologica (2008), 93(2), 240-7
BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning ... [more ▼]
BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning. DESIGN AND METHODS: Fifty patients were randomized to receive either CD8-depleted (n=22) or non-manipulated (n=28) peripheral blood stem cells. The median patients age was 57 (range 36-69) years. The conditioning regimen consisted of 2 Gy total body irradiation with or without added fludarabine. Twenty patients received grafts from related donors, 14 from 10/10 HLA-allele matched unrelated donors, and 16 from HLA-mismatched unrelated donors. Graft-versus-host disease pro-phylaxis consisted of mycophenolate mofetil and cyclosporine. Immune recovery during the first year after hematopoietic cell transplantation was assessed by flow cytometry phenotyping, analyses of the diversity of the TCRBV repertoire, and quantification of signal-joint T-cell receptor excision circles (sjTREC). RESULTS: CD8-depletion of the graft reduced the recovery of CD8(+) T-cell counts in the first 6 months following transplantation (p<0.0001) but had no significant impact on the restoration of other T-cell subsets. Both sjTREC concentration and CD3(+) T-cell counts increased significantly between day 100 and 365 (p=0.010 and p=0.0488, respectively) demonstrating neo-production of T cells by the thymus. Factors associated with high sjTREC concentration 1 year after transplantation included an HLA-matched unrelated donor (p=0.029), a high content of T cells in the graft (p=0.002), and the absence of chronic graft-versus-host disease (p<0.0001). CONCLUSIONS: Our data suggest that while immune recovery is mainly driven by peripheral expansion of the graft-contained mature T cells during the first months after non-myeloablative transplantation, T-cell neo-generation by the thymus plays an important role in long term immune reconstitution in transplanted patients. [less ▲]Detailed reference viewed: 159 (85 ULg)
Comment je traite...La leucémie myéloblastique aiguë (LMA) du sujet age en bon état général.
Lejeune, Marie ; Beguin, Yves ; De Prijck, Bernard et al
in Revue Médicale de Liège (2008), 63(2), 59-63
This article describes the treatment of acute myeloid leukemia in older patients with good performance status, and then discusses briefly some future therapeutic perspectives.Detailed reference viewed: 168 (11 ULg)
Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning
Baron, Frédéric ; ; 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 ▲]Detailed reference viewed: 86 (0 ULg)
Hematopoietic cell transplantation after reduced-intensity conditioning for older adults with acute myeloid leukemia in complete remission
Baron, Frédéric ;
in Current Opinion in Hematology (2007), 14(2), 145-151
Purpose of review Allogeneic hematopoietic cell transplantation with myeloablative conditioning is a well established therapy for patients with acute myeloid leukemia. Its efficacy depends, in part, on ... [more ▼]
Purpose of review Allogeneic hematopoietic cell transplantation with myeloablative conditioning is a well established therapy for patients with acute myeloid leukemia. Its efficacy depends, in part, on the destruction of recipient acute myeloid leukemia cells by the conditioning regimen and, in part on their removal by donor immune cells contained in the graft (graft-versus-tumor effect). Due to regiment related toxicities, the use of myeloablative allogeneic hematopoietic cell transplantation has been restricted to younger patients in good condition. More recently, the introduction of allogeneic hematopoietic cell transplantation following reduced-intensity or nonmyeloablative conditioning regimens, which rely mainly on graft-versus-tumor effects for tumor cell eradication, has permitted extending hematopoietic cell transplantation to include older patients and those with medical comorbidities. Recent findings Early results with allogeneic hematopoietic cell transplantation after nonmyeloablative and reduced-intensity conditioning for patients with acute myeloid leukemia in first complete remission are encouraging, with 2-year survivals after hematopoietic cell transplantation ranging from 48 to 79% among studies. Further, retrospective studies have demonstrated similar outcomes in adult patients with acute myeloid leukemia in complete remission given either myeloablative or nonmyeloablative conditioning. Summary Prospective studies are needed to define the place of allogeneic hematopoietic cell transplantation after nonmyeloablative or reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission, and to determine a role for consolidation chemotherapy before hematopoietic cell transplantation, if any. [less ▲]Detailed reference viewed: 334 (1 ULg)
What is the role for donor NK cells after nonmyeloablative conditioning ?
Baron, Frédéric ; ; et al
in Blood (2007), 110
Background: The potential role of donor NK cells after nonmyeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT) is not defined. We investigated the impact of the kinetics of ... [more ▼]
Background: The potential role of donor NK cells after nonmyeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT) is not defined. We investigated the impact of the kinetics of donor NK cell engraftment as well as the impact of missing recipient KIR ligands and the number of donor inhibitory and activating KIR genes on HCT outcomes in 282 patients (153 with HLA-matched related donors and 129 with unrelated donors) conditioned with 2 Gy TBI +/– fludarabine. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Diagnoses were hematological malignancies (n=274) or solid tumors (8). Methods: NK cells were isolated from peripheral blood by flow cytometry on days 14, 28 and 42 after HCT. The proportions of cells of donor and host origin were assessed by FISH or by VNTR-PCR. High-resolution HLA-typing was performed using oligonucleotide probe and/or direct sequencing methods. Donor KIR genotyping was performed using a commercial PCR-SSP kit (Invitrogen) following manufacturers protocol. Results: High numbers of T (P=0.01) and CD34+ (P=0.009) cells in the graft, as well as lower numbers of donor inhibitory KIR genes (P=0.01) were each associated with higher levels of donor NK cell chimerism. There was a suggestion of an association between lower numbers of activating KIR genes and higher CD56 chimerism, however this was not statistically significant. NK cell chimerism levels were comparable in patients who had all KIR ligands present vs. in those who were missing any ligand, and there was no association between the specific missing ligand and NK chimerism. A day-14 NK cell chimerism level of < 50% was associated with increased risks of graft rejection (P=.009). Modeling chimerism levels as a continuous linear variable, there was no association between NK cell chimerism levels on day 14 and occurrence of grade II-IV acute GVHD. In contrast, high levels of donor NK cell chimerism on days 14–42 were associated with a lower risk of relapse (P=0.006) and better progression-free survival (P=0.003) in time-dependent analyses. The qualitative associations between donor NK cell chimerism and graft rejection, GVHD, relapse or progression-free survival did not change after adjustment for the presence of recipient KIR ligands nor after adjustment for the number of donor inhibitory or activating KIR genes. Finally, the 3-year cumulative incidence of relapse was 42% in patients who have all ligand for donor NK cell KIR, versus 38% in patients who miss one or more ligand for donor NK cell KIR (adjusted hazard ratio = 1.05; 95% confidence interval 0.65–1.68; p=0.85). Conclusions: Robust engraftment of donor NK cells correlated with low risk of graft rejection, low risk of relapse and high progression-free survival but not with acute GVHD. The clinical importance of donor KIR inhibitory and activating genes on post-transplant donor NK chimerism merits further study. Footnotes Disclosure: Off Label Use: Fludarabine, Mycophenolate mofetil, Cyclosporine. [less ▲]Detailed reference viewed: 1 (0 ULg)