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Superior GVHD-free, relapse-free survival for G-BM to G-PBSC grafts is associated with higher MDSCs content in allografting for patients with acute leukemia
Background
Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (G-PBSC) has largely replaced unstimulated bone marrow (un-BM) for allografting because of accelerated engraftment, but with a higher morbidity and mortality of graft-versus-host-disease (GVHD). Recent studies suggested that G-CSF-primed BM (G-BM) had similar engraftment but lower morbidity and mortality of GVHD comparing to G-PBSC. A prospective, randomized, multicenter study was conducted to compare G-BM with G-PBSC as the grafts in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia in first complete remission (CR1).
Methods
Totally 101 adult leukemia in CR1 undergoing HLA-identical sibling transplants were randomized into G-BM or G-PBSC group. The primary study endpoint was GVHD-free/relapse-free survival (GRFS).
Results
Both the engraftment of neutrophil and platelet were 2 days later in G-BM than in G-PBSC group (
P
= 0.412,
P
= 0.39). G-BM group showed significantly lower II–IV acute GVHD (aGVHD) and similar III–IV aGVHD compared with G-PBSC group (12.2% vs 28.8% for II–IV,
P
= 0.048; 4.1% vs 9.6% for III–IV aGVHD,
P
= 0.267, respectively). The overall cumulative incidence of chronic GVHD (cGVHD) at 3 years were 22.3% ± 6.3% and 44.8% ± 7.6% (
P
= 0.026), respectively, and extensive cGHVD were 4.5% ± 3.1% and 15% ± 5.3% (
P
= 0.08), respectively, in G-BM and G-PBSC groups. Two groups had similar 3-year relapse, transplant-related mortality (TRM), overall survival (OS), and disease-free survival (DFS) (all
P
> 0.05). G-BM group showed significantly higher probability of GRFS than G-PBSC group (73.5% ± 6.3% vs 55.8% ± 6.9% at 1 year,
P
= 0.049; 69.0% ± 6.7% vs 49.7% ± 7.0% at 2 and 3 years,
P
= 0.03, respectively). Graft content analysis revealed statistically higher frequency of myeloid-derived suppressor cells (MDSCs) in the G-BM than in G-PBSC grafts (
P
< 0.01), and recipients received statistically higher numbers of MDSCs in G-BM than in G-PBSC group (
P
= 0.045). Numbers of MDSCs infused to patients were negatively correlated with the severity of aGVHD (
P
= 0.032,
r
= −0.214). Multivariate analysis showed that MDSC cell dose below the median (HR = 3.49,
P
< 0.001), recipient age (HR = 2.02,
P
= 0.039), and high risk of disease (HR = 2.14,
P
= 0.018) were independent risk factors for GRFS.
Conclusions
G-BM grafts lead a better GRFS and less GVHD associated with a higher MDSCs content compared with G-PBSC grafts.
Journal Article
Introduction to organ transplantation
\"This second edition of the introduction to the field of organ transplantation provides an excellent overview of the tremendous progress made in recent decades, and gives a clear description of the current status of transplant surgery for students and trainees with an interest in this field. It opens with introductory chapters on the history of transplantation and the basic science of immunobiology, and then examines through an organ-based structure the practice of transplantation in each major system, from skin to intestine. This is a timely publication produced in line with the rapidly advancing field of transplantation.\" -- Publisher.
Book
Co-infusion of mesenchymal stromal cells to prevent GVHD after allogeneic hematopoietic cell transplantation from HLA-mismatched unrelated donors after reduced-intensity conditioning: a double-blind randomized study and literature review
Background
Mesenchymal stromal cells (MSC) have immunomodulatory and hematopoiesis-supporting properties that could potentially benefit hematopoietic stem cell (HSC) engraftment and decrease the incidence and/or severity of graft-versus-host disease (GVHD).
Methods
Based on our previous pilot study, we established a multicenter, prospective, randomized, double-blind trial evaluating the efficacy of co-infusing third-party MSC (1.5–3 × 10
6
/kg) versus placebo on the day of HSC transplantation (HCT) to prevent GVHD in recipients of HLA-mismatched unrelated donors after reduced-intensity conditioning.
Results
The study planned to include 120 patients to improve 1-year overall survival (OS) from 55 to 77% but was stopped after 9 years for low recruitment (n = 38). One-year OS was 74% in the MSC group and 80% in the placebo group. In multivariate analysis, the incidence of grade II-IV acute GVHD was significantly lower in patients receiving MSC (HR 0.332, 95% CI 0.124–0.890,
p
= 0.0284). No difference was observed in the incidences of chronic GVHD, infection or relapse, overall or progression-free survival at 1 year or long-term, or hematopoietic and immune reconstitution.
Conclusions
Despite premature study closure, the suggested beneficial effect of MSC co-transplantation for the prevention of acute GVHD in HLA-mismatched HCT warrants further investigation.
Journal Article
Feasibility of reduced-dose posttransplant cyclophosphamide and cotransplantation of peripheral blood stem cells and umbilical cord-derived mesenchymal stem cells for SAA
Posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis is an effective strategie for patients receiving matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and haploidentical HSCT (haplo-HSCT). We evaluated the effectiveness and safety of reduced-dose cyclophosphamide, 20 mg/kg for 13 patients in MSD-HSCT cohort and 25 mg/kg for 22 patients in haplo-HSCT cohort, on days + 3, + 4 combined with cotransplantation of peripheral blood stem cells (PBSCs) and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for severe aplastic anemia (SAA). In MSD-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the MSD-control cohort (P < 0.05). The cumulative incidence of acute GVHD (aGVHD) at day + 100 (15.4%) was lower than that in the MSD-control cohort (P = 0.050). No patient developed chronic GVHD (cGVHD). The 1-year overall survival (OS) and event-free survival (EFS) rates were 100% and 92.3%. In haplo-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the haplo-control cohort (P < 0.05). The cumulative incidences of aGVHD at day + 100 and 1-year cGVHD were 31.8% and 18.2%, and the 1-year OS and EFS rates were 81.8% and 66.9%. Reduced-dose PTCy and cotransplantation of PBSCs and UC-MSCs is an acceptable alternative to patients with SAA.
Journal Article
Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients
We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m
2
once daily x4, each dose followed by IV Bu, randomized to 130 mg/m
2
(
N
=107) or PK-guided to average daily SE, AUC of 6000 μ
M
min (
N
=111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.
Journal Article
Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: A Pediatric Blood and Marrow Transplant Consortium study
Conditioning regimens for children with ALL have generally included total body irradiation (TBI), which may result in significant sequelae. The primary aim of this study was to evaluate the outcome for children with ALL undergoing allogeneic stem cell transplant (SCT) with either busulfan (Bu) or TBI regimens. Patients <21 years with ALL undergoing allogeneic SCT were eligible. Conditioning included either Bu or TBI, with etoposide 40 mg/kg and cyclophosphamide 120 mg/kg. Randomization was stratified based upon duration of remission, remission status, and prior cranial irradiation. A total of 43 patients were enrolled; 21 received Bu and 22 TBI. Median patient age was 8 years (0.5-20 years). Remission status included 12 patients in CR1, 25 in CR2, and six in CR3. At a median follow-up of 43 months, event-free survival (EFS) is 45% at 3 years, with 29% EFS in the Bu arm and 58% in the TBI arm (P=0.03). There was no significant difference between Bu and TBI for patients who received stem cells from related donors (36 vs 58%, P=0.3). However, for URD, EFS was 20% for Bu and 57% for TBI (P=0.04). Relapses were similar in both arms. This randomized prospective study suggests that Bu is inferior to TBI for pediatric patients with ALL undergoing allogeneic SCT.
Journal Article