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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 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 detailIntensified postgrafting immunosuppression failed to assure long-term engraftment of dog leukocyte antigen-identical canine marrow grafts after 1 gray total body irradiation.
Sorror, Mohamed L; Leisenring, Wendy; Mielcarek, Marco 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 ▲]

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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 detailWhat is the role for donor NK cells after nonmyeloablative conditioning ?
Baron, Frédéric ULg; Petersdorf, Effie; Sandmaier, Brenda 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 ▲]

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See detailComorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation.
Sorror, Mohamed L; Sandmaier, Brenda M; Storer, Barry E et al

in Journal of Clinical Oncology (2007), 25(27), 4246-54

PURPOSE: Retrospective studies have shown similar survival among patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) after nonmyeloablative compared with myeloablative conditioning ... [more ▼]

PURPOSE: Retrospective studies have shown similar survival among patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) after nonmyeloablative compared with myeloablative conditioning. Refined risk stratification is required to design prospective trials. PATIENTS AND METHODS: We stratified outcomes among patients with AML (n = 391) or MDS (n = 186) who received either nonmyeloablative (n = 125) or myeloablative (n = 452) allogeneic hematopoietic cell transplantation (HCT) based on comorbidities, as assessed by a HCT-specific comorbidity index (HCT-CI), as well as disease status. Patients receiving nonmyeloablative conditioning were older, more frequently pretreated, more often received unrelated grafts, and more often had HCT-CI scores of 3 compared with patients who received myeloablative conditioning. RESULTS: Patients with HCT-CI scores of 0 to 2 and either low or high disease risks had probabilities of overall survival at 2 years of 70% and 57% after nonmyeloablative conditioning compared with 78% and 50% after myeloablative conditioning, respectively. Patients with HCT-CI scores of 3 and either low or high disease risks had probabilities of overall survival of 41% and 29% with nonmyeloablative conditioning compared with 45% and 24% with myeloablative regimens, respectively. After adjusting for pretransplantation differences, stratified outcomes were not significantly different among patients receiving nonmyeloablative compared with myeloablative conditioning, with the exception of lessened nonrelapse mortality (hazard ratio, 0.50; P = .05) in the highest risk group. CONCLUSION: Patients with low comorbidity scores could be candidates for prospective randomized trials comparing nonmyeloablative and myeloablative conditioning regardless of disease status. Additional data are required for patients with low-risk diseases and high comorbidity scores. Novel antitumor agents combined with nonmyeloablative HCT should be explored among patients with high comorbidity scores and advanced disease. [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 detailThe immune system as a foundation for immunologic therapy and hematologic malignancies: a historical perspective.
Baron, Frédéric ULg; Storb, Rainer

in Bailliere's Best Practice & Research. Clinical Haematology = Best Practice & Research. Clinical Haematology (2006), 19(4), 637-53

In this review we aim to provide a historical overview of the immunotherapeutic approaches which have been developed for the treatment of hematological malignancies. After briefly summarizing the ... [more ▼]

In this review we aim to provide a historical overview of the immunotherapeutic approaches which have been developed for the treatment of hematological malignancies. After briefly summarizing the development of the theory of cancer immune surveillance, we describe how initial studies discovering the efficacy of the immune-mediated graft-versus-tumor effects after allogeneic hematopoietic cell transplantation led to new transplantation approaches (termed non-myeloablative transplantation) relying almost exclusively on graft-versus-tumor effects for tumor eradication. We then summarize important steps in the development of tumor vaccines and autologous adoptive immunotherapy in patients with hematological malignancies. Finally, we describe historical discoveries leading to the recent success with monoclonal antibodies as treatment for lymphomas, chronic lymphocytic leukemia, and acute myeloid leukemia. [less ▲]

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See detailExtending postgrafting cyclosporine decreases the risk of severe graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation
Burroughs, Lauri; Mielcarek, Marco; Leisenring, Wendy et al

in Transplantation (2006), 81(6), 818-25

BACKGROUND: It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity ... [more ▼]

BACKGROUND: It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity, timing, and/or corticosteroid-responsiveness of graft-versus-host disease (GVHD). METHODS: We retrospectively analyzed outcomes among 185 patients with hematologic malignancies who were given grafts from HLA-matched related donors following conditioning with 2 Gy total body irradiation alone or in combination with fludarabine between December 1998 and March 2003. Postgrafting immunosuppression consisted of mycophenolate mofetil (days 0-27) in combination with 3 different cyclosporine (CSP) regimens: taper from (A) days 35 to 56 (n=107), (B) days 56 to 77 (n=35), and (C) days 56 to 180 (n=43). RESULTS: The overall incidences of grades II-IV and III-IV acute GVHD, and extensive chronic GVHD were 52%, 13%, and 56%, respectively. The duration of CSP prophylaxis did not significantly influence the overall rate of acute GVHD (grade II-IV), extensive chronic GVHD, or non-relapse mortality. However, prolonged administration of CSP (group C) was associated with a significantly decreased hazard of grades III-IV acute GVHD (HR 0.2, 95% CI [0.04, 0.9]) and with an increased likelihood of discontinuing all systemic immunosuppression (HR 2.4, 95% CI [1.1, 5.2]) when compared to the shortest course of CSP (group A). CONCLUSION: Longer CSP duration decreased the risk of severe GVHD and increased the likelihood of discontinuing all systemic immunosuppression after nonmyeloablative HCT with HLA-matched related grafts. [less ▲]

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See detailKinetics of engraftment following allogeneic hematopoietic cell transplantation with reduced-intensity or nonmyeloablative conditioning.
Baron, Frédéric ULg; Little, Marie-Terese; Storb, Rainer

in Blood Reviews (2005), 19(3), 153-64

Nonmyeloablative or reduced-intensity conditioning regimens have been used to condition elderly or ill patients with hematological malignancies for allogeneic hematopoietic cell transplantation (HCT ... [more ▼]

Nonmyeloablative or reduced-intensity conditioning regimens have been used to condition elderly or ill patients with hematological malignancies for allogeneic hematopoietic cell transplantation (HCT). Initial mixed donor/host chimerism (i.e. the coexistence of hematopoietic cells of host and donor origin) has been observed in most patients after such transplants. Here, we describe both factors affecting engraftment kinetics in patients given a nonmyeloablative or a reduced-intensity conditioning, and associations between peripheral blood cell subset chimerism levels and HCT outcomes. [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 detailHematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.
Sorror, Mohamed L; Maris, Michael B; Storb, Rainer et al

in Blood (2005), 106(8), 2912-9

We previously reported that the Charlson Comorbidity Index (CCI) was useful for predicting outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). However, the sample size of ... [more ▼]

We previously reported that the Charlson Comorbidity Index (CCI) was useful for predicting outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). However, the sample size of patients with scores of 1 or more, captured by the CCI, did not exceed 35%. Further, some comorbidities were rarely found among patients who underwent HCT. Therefore, the current study was designed to (1) better define previously identified comorbidities using pretransplant laboratory data, (2) investigate additional HCT-related comorbidities, and (3) establish comorbidity scores that were suited for HCT. Data were collected from 1055 patients, and then randomly divided into training and validation sets. Weights were assigned to individual comorbidities according to their prognostic significance in Cox proportional hazard models. The new index was then validated. The new index proved to be more sensitive than the CCI since it captured 62% of patients with scores more than 0 compared with 12%, respectively. Further, the new index showed better survival prediction than the CCI (likelihood ratio of 23.7 versus 7.1 and c statistics of 0.661 versus 0.561, respectively, P < .001). In conclusion, the new simple index provided valid and reliable scoring of pretransplant comorbidities that predicted nonrelapse mortality and survival. This index will be useful for clinical trials and patient counseling before HCT. [less ▲]

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See detailCurrent roles for allogeneic hematopoietic cell transplantation following nonmyeloablative or reduced-intensity conditioning.
Baron, Frédéric ULg; Storb, Rainer

in Clinical Advances in Hematology & Oncology (2005), 3(10), 799-819

Nonmyeloablative and reduced-intensity conditioning regimens followed by allogeneic hematopoietic cell transplantation (HCT) have been evaluated in patients with hematologic malignancies who were not ... [more ▼]

Nonmyeloablative and reduced-intensity conditioning regimens followed by allogeneic hematopoietic cell transplantation (HCT) have been evaluated in patients with hematologic malignancies who were not considered candidates for conventional HCT because of age or medical comorbidities and in selected patients with metastatic renal cell carcinoma. The regimens have relied more on graft-versus-tumor effects than on chemoradiation therapy to facilitate engraftment and eradicate malignant cells. While nonmyeloablative HCT has been associated with reduced regimen-related toxicities and has been curative for a number of patients with hematologic malignancies, challenges have remained in regard to graft-versus-host disease, infections, and disease progression. In this article, we review data from a number of published phase I and II studies that describe the results of allogeneic HCT after nonmyeloablative conditioning. [less ▲]

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See detailGraft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning
Baron, Frédéric ULg; Maris, Michael; Sandmaier, Brenda et al

in Blood (2004), 104

We have used a nonmyeloablative conditioning regimen consisting of 2 Gy total body irradiation +/– fludarabine, 30 mg/m²/day x 3 days, to condition elderly or ill patients (pts) with hematological ... [more ▼]

We have used a nonmyeloablative conditioning regimen consisting of 2 Gy total body irradiation +/– fludarabine, 30 mg/m²/day x 3 days, to condition elderly or ill patients (pts) with hematological malignancies for allogeneic hematopoietic cell transplantation (HCT). This approach relies almost exclusively on graft-versus-tumor (GVT) effects for control of malignancy. Here, we analyzed GVT effects in 322 pts with hematological malignancies given grafts from HLA-matched related (n=192) or unrelated (n=130) donors. Grades I, II, III and IV acute GVHD were seen in 26 (8.1%), 141 (43.8%), 34 (10.6%) and 11 (3.4%) pts, respectively. Extensive chronic GVHD was seen in 181 (56.2%) pts and of these, 64 (19.9%) cases had de novo chronic GVHD. Putative GVT effects were evaluated using time-dependent Cox regression models. Of the 221 pts with measurable disease at HCT, 126 (57%) achieved complete (n=98) or partial (n=28) remissions. Multivariate analysis identified chemosensitivity for B-cell malignancies (p=.02), and tandem autologous/allogeneic HCT (p=.04) as pre-transplant factors associated with higher probabilities of achieving complete remissions (CR) after HCT. After adjusting for these factors, acute GVHD of any grade was not found to be associated with an increased probability of achieving CR. There was a trend for a higher probability of achieving CR in pts with chronic GVHD (p=.07). Progression/relapse was observed in 108 pts. Multivariate analysis identified that lower disease-risk (p=.0004), tandem autologous/allogeneic HCT (p=.02) and adapted Charlson comorbidity index (CCI) score at transplant < 3 (p=.002) resulted in significantly decreased risk of progression/relapse. After correcting for these factors, extensive chronic GVHD was associated with a decreased risk of progression/relapse (p=.006). Pts with grade 1 acute GVHD tended to have less progression/relapse (p=.07). Conversely, grade II–IV acute GVHD did not significantly affect the risk of progression/relapse. Nonrelapse mortality was observed in 70 pts. Multivariate analysis showed that lower disease-risk (p=. 001), tandem autologous/allogeneic HCT (p=.002) and CCI score at transplant < 3 (p<.0001) significantly decreased nonrelapse mortality. After adjusting for these variables, grade II (p=.04) and grade III–IV (p<.0001) acute GVHD increased nonrelapse mortality while extensive chronic GVHD did not. The 3-year probability of progression-free survival (PFS) was 38.5%. In multivariate analysis, lower disease-risk (p<.0001), tandem autologous/allogeneic HCT (p=.0008) and CCI score at transplant < 3 (p<.0001) resulted in significantly better PFS. After adjusting for theses variables, grade 1 acute GVHD (p=.02) and chronic extensive GVHD (p=.003) were both associated with significantly better PFS, while grade III–IV acute GVHD (p<.0001) was associated with decreased PFS. In summary, chronic GVHD in pts given nonmyeloablative conditioning was associated with substantial GVT effects which led to improved PFS. Conversely, any potential GVT benefits from grade II–IV acute GVHD were offset by higher nonrelapse mortality resulting in worse PFS. Efforts should be directed at reducing the risk of grade II–IV acute GVHD while allowing de novo chronic GVHD for best PFS after allogeneic HCT with nonmyeloablative conditioning. [less ▲]

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See detailAllogeneic hematopoietic cell transplantation as treatment for hematological malignancies: a review.
Baron, Frédéric ULg; Storb, Rainer

in Springer Seminars in Immunopathology (2004), 26(1-2), 71-94

Allogeneic hematopoietic cell transplantation (HCT) was originally developed as a form of rescue from high-dose chemoradiotherapy, which is given both to eradicate malignancy and provide sufficient ... [more ▼]

Allogeneic hematopoietic cell transplantation (HCT) was originally developed as a form of rescue from high-dose chemoradiotherapy, which is given both to eradicate malignancy and provide sufficient immunosuppression for allogeneic engraftment. The first attempts of allogeneic HCT in humans met with little success. However, a better understanding of the complexities of the human leukocyte antigen (HLA) system has allowed selecting compatible sibling donors, and the development of postgrafting immunosuppressive regimens has helped prevent serious graft-versus-host disease, thereby changing the role of allogeneic HCT from a desperate therapeutic maneuver to a curative treatment modality for many patients with malignant hematological diseases. In addition, the establishment of large registries of HLA-typed volunteers has permitted finding suitable unrelated donors for many patients without family donors. Further advances in the immunogenetics of HLA, especially typing by molecular techniques, have improved results after unrelated HCT, which have begun resembling those obtained with HLA-identical sibling grafts, at least in young patients. Important advances have also been made in the prevention and treatment of infectious complications and in other areas of supportive care. Since the late seventies, it has been recognized that allogeneic immunocompetent cells transplanted with the stem cells, or arising from them, mediated therapeutic anti-tumor effects independent of the action of the high-dose therapy, termed graft-versus-tumor (GVT) effects. This has prompted the recent development of non-myeloablative conditioning regimens for allogeneic HCT that have opened the way to include elderly patients and those with comorbid conditions. Remaining challenges include further advances in the prevention and treatment of both severe graft-versus-host disease and infections. Also, progress in adoptive transfer of T cells with relative tumor specificity and disease-targeted therapy with agents such as Imatinib, Rituximab or radiolabeled monoclonal antibodies would make allogeneic HCT even more effective. [less ▲]

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See detailKinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.
Baron, Frédéric ULg; Baker, Jennifer E.; Storb, Rainer et al

in Blood (2004), 104(8), 2254-62

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic ... [more ▼]

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression. [less ▲]

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See detailHematopoietic cell transplantation: five decades of progress.
Baron, Frédéric ULg; Storb, Rainer; Little, Marie-Terese

in Archives of Medical Research (2003), 34(6), 528-44

During the past 50 years, the role of allogeneic hematopoietic cell transplantation (HCT) has changed from a desperate therapeutic maneuver plagued by apparently insurmountable complications to a curative ... [more ▼]

During the past 50 years, the role of allogeneic hematopoietic cell transplantation (HCT) has changed from a desperate therapeutic maneuver plagued by apparently insurmountable complications to a curative treatment modality for thousands of patients with hematologic diseases. Now, cure rates following human leukocyte antigen (HLA) allogeneic HCT with matched siblings exceed 85% for some otherwise lethal diseases, such as chronic myeloid leukemia, aplastic anemia, or thalassemia. In addition, the recent development of non-myeloablative conditioning and stem cell transplantation has opened the way to include elderly patients with a wide variety of hematologic malignancies. Further progress in adoptive transfer of T cell populations with relative tumor specificity would make the transplant procedure more effective and would extend the use of allogeneic HCT for treatment of non-hematopoietic malignancies. [less ▲]