Donor Inflammatory Gene Polymorphisms Are Associated with Early Bacterial Infection After Unrelated Allogeneic Haematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1159-1159
Author(s):  
Haowen Xiao ◽  
Xiaoyu Lai ◽  
Gongqiang Wu ◽  
Yi Luo ◽  
Jimin Shi ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Gene Polymorphisms ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
T Cell Response ◽  
Early Infection ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Significant Difference

Abstract Abstract 1159 Poster Board I-181 Background In allogeneic SCT, genetic factors such as donor and recipient gene polymorphisms of pro- and anti-inflammatory cytokines have been associated with the incidence and severity of GVHD. However, the influence of such donor and recipient gene polymorphisms on other outcomes, such as early infection after SCT, has seldom been described. TNFαa, TNF receptorII (TNFRII), IL-10 and TGF gene contain multiple single nucleotide polymorphisms (SNPs) in the promoter and codon region. We thus studied the association of this panel of candidate gene polymorphisms with the incidence of the first episodes of early bacterial infections within 100 days after allo-HSCT. Methods A total of 138 unrelated donor/recipient pairs, who had undergone HLA-matched allo-HSCT from January 2001 to March 2009 at the First Affiliated Hospital of Zhejiang University School of Medicine, were tested for TNFαa(TNFαa-857 C>T, TNFαa-863 C>A, TNFαa-1031 T>C), TNFRII (codon196 T>G), IL-10 (IL10-1082 A>G, IL10-819 T>C, IL10-592 A>C), TGF (TGF-509 T>C, TGF+869 C>T) polymorphism allele frequencies and genotype. SNPs were analysed by Multiplex SnaPshot. We considered the first episodes of early bacterial infections within 100 days after allo-HSCT have developed when sepsis, pneumonia, or septic shock was diagnosed according to previously published criteria. Results (1) 133 patients achieved complete donor chimerism in the peripheral blood and 5 patients had graft failure. All patients achieved an absolute neutrophil count (ANC) greater than 0.5×109/L at day 13 (7∼22) and platelet recovery at day 15 (7∼64). The cumulative incidence of at least one bacterial infection was 47.8% (pneumonia and intestinal infection are the most popular) within 100 days after allo-HSCT. There is no significant difference in the time to neutrophil recovery in patients who experienced early bacterial infections with those who did not (13.6 vs 12.8,P=0.115). (2) The TNFαa-857 C/C genotype and TNFRII 196 T/T genotype of the donor were significantly associated with a higher risk of early bacterial infection ( for TNFαa-857 C/C genotype: 53.3% vs 29.0%, P=0.024 ; TNFRII 196 T/T genotype: 53.5% vs 33.3%, P=0.038); (3) The TGF-509 T/T genotype of the donor was significantly associated with a higher risk of early bacterial infection (62.5% vs 41.8, P=0.038); (4) Transplantation from donors with IL10-819 C/C genotype or IL10-592 C/C genotype were significantly associated with a higher risk of early bacterial infection (for IL10-819 C/C genotype: 71.4.1% vs 45.3%, P=0.034; IL10-592 C/C genotype: 70.0.1% vs 45.8%, P=0.055); (5) The genotypes of TNFαa-863, TNFαa-1031, IL10-1082 and TGF+869 were not found to be associated with the risk of early bacterial infection. Conclusions Recent studies have shown that the generation potential of IL-10 is influenced by the polymorphism of the IL-10 gene. The IL10-819*C allele and IL10-592 *C allele are associated with higher secretion of IL-10 than IL10-819*T allele and IL10-592*A allele. In our data, a higher risk of early bacterial infection with IL10-819 C/C and IL10-592 C/C genotype was postulated to be associated with a higher IL-10 production, which suppressed reactive T-cell response. These results, which is the first report of TNFαa, TNFRII, IL-10and TGF polymorphic features of Chinese population with the risk of early bacterial infection after HLA-matched unrelated allo-HSCT, suggest an interaction of the donor TNFαa-857C/C, TNFRII 196 T/T, IL10-819 C/C, IL10-592 C/C and TGF-509 T/T genotypes on risk of early infection. These results are helpful for predict allo-HSCT outcome, identify more suitable donors and clarify therapy on an individual patient basis. Disclosures No relevant conflicts of interest to declare.

Heparin-Induced Thrombocytopenia Antibody Is More Common in Patients with Active Bacterial Infections

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4678-4678
Author(s):  
Melody Smith ◽  
Prapti A. Patel ◽  
Jonathan E Dowell ◽  
Eugene P. Frenkel ◽  
Ravindra Sarode ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Subgroup Analysis ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Heparin Induced Thrombocytopenia ◽  
E Coli ◽  
Significant Difference

Abstract Abstract 4678 Heparin mobilizes and binds to platelet factor 4 (PF4), forming a heparin-PF4 complex on the platelet surface. Rarely, IgG antibodies recognize and bind to the immune complex, causing platelet activation and thrombin generation, resulting in heparin induced thrombocytopenia (HIT). There is evidence that PF4 has a role in antibacterial host defense and can concurrently prime the immune system with IgG antibodies that can cross-react with the heparin-PF4 complex (Krauel et al, Blood 2011). In the setting of a bacterial infection, the PF4 molecules interact with the bacterial cell wall and induce antibody production. These antibodies are able to recognize any bacteria coated in PF4, resulting in phagocytosis. In the setting of heparin, this antibody can cross react with the heparin-PF4 complex and result in HIT. In vitro studies suggest that E. coli, S. pneumo, and S. aureus coated in PF4 cross-react with human heparin induced anti-PF4/heparin antibodies. We have collected a database of patients being tested for HIT at our institution and performed a retrospective analysis of the incidence of bacterial infections. We hypothesize that patients who have a bacterial infection will be more likely to develop HIT due to anti-bacterial antibodies that cross-react with the heparin-PF4 complex. We collected culture data from 54 patients with positive HIT antibody by ELISA and 178 patients with negative HIT antibody. The incidence of positive cultures and active infections in described in table 1. In the HIT negative patients, 61/178 (34.3%) had positive cultures, compared to 28/54 (51.9%) in the HIT positive patients (p=0.0198). Given that there is data to support E. coli, S. pneumo, and S. aureus-induced antibody cross-reactivity, we performed a subgroup analysis of the incidence of these specific bacterial infection in HIT positive and negative patients (33.3% versus 19.7%, p=0.0357). There is a statistically significant difference noted in the active infections, subgroup analysis, as well presence of any positive cultures in the HIT positive patients as compared to the HIT negative patients.Table 1Colonized Infections (%)Active Infections (%)E. coli, S. pneumo, S. aureus (%)Any + culture (%)HIT negative (n=178)15 (8.4)61 (34.3)35 (19.7)66 (37.1)HIT positive (n=54)2 (3.7)28 (51.9)18 (33.3)29 (53.7)p value0.2420.01980.03570.0293 This data supports that in the setting of active infection, particularly with E. coli, S. pneumo, and S. aureus, HIT antibody results should be carefully evaluated. Patients with positive cultures are likely to have thrombocytopenia from infection or sepsis, regardless of the presence of a HIT antibody. Thus, additional factors, such as the patient's 4T score and the presence of thrombosis should be considered prior to initiating treatment for HIT. Disclosures: No relevant conflicts of interest to declare.

Prolonged Transportation Time Of Haemopoietic Progenitor Cells Does Not Impact Upon Engraftment Or Overall Survival Following Allogeneic Voluntary Unrelated Donor Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 694-694
Author(s):  
Cheryl J Hutchins ◽  
Jason P Butler ◽  
Angela McLean ◽  
Judith Y Cummings ◽  
Geoff R Hill ◽  
...  
Keyword(s):  
Overall Survival ◽  
Progenitor Cells ◽  
Transit Time ◽  
Conflicts Of Interest ◽  
Unrelated Donor ◽  
Allogeneic Transplant ◽  
Platelet Recovery ◽  
Transplant Centre ◽  
Transit Times ◽  
Significant Difference

Abstract Introduction The transportation of haemopoietic progenitor cells (HPC) from collection centre to transplant centre is a critical, but often overlooked process during allogeneic transplantation using voluntary unrelated donors (VUD). The policies of international donor registries support the rapid retrieval and infusion of HPC. However transplant centres are often challenged by transit times in excess of 24h when retrieving HPC from intercontinental collection centres. This single institutional retrospective study aimed to investigate if a prolonged transit time between collection and transplant centre impacted upon the rate of engraftment and overall survival of recipients of HPC collected from VUDs. Methodology A retrospective analysis of outcomes following an initial allogeneic transplant performed at our institution between 1987 and 2013 was conducted using institutional databases. The time to neutrophil and platelet engraftment and overall survival was compared between recipients of VUD transplants with HPC retrieved from collection centres located overseas (transit time of > 24h) (n = 241; BM n = 50, PBPC n = 191), recipients of unrelated donor transplants with HPC retrieved from collection centres within Australia (transit time of <8h) (n = 334; BM n = 112, PBPC n = 222) and recipients of related HPC collected at the transplant centre (n = 807; BM n = 320, PBSC n = 487). All HPC retrieved from local and intercontinental VUD collection centres were transported in rigid coolers containing refrigerated gel packs prior to 2003 or isothermal cooling inserts post 2003. The temperature was monitored and maintained by the courier at between 2 and 8oC. Results There was no significant difference in the days to neutrophil and platelet recovery (Table 1) between recipients of a VUD allogeneic transplant with HPC retrieved from a local collection centre compared with those recipients whose HPC was retrieved from an international collection centre. Retrieval and infusion of HPC from local collection centres is generally completed within 8h from collection whereas the interval from collection to infusion may vary between 24 to 90h when HPC are retrieved from intercontinental collection centres. Furthermore there was no significant difference in overall survival (Figure 1) of recipients of related donor allogeneic transplants performed without transportation of HPC and recipients of VUD allogeneic transplants whose HPC were retrieved from either a local collection centre or an intercontinental collection centre (Figure 1). Conclusion Our study demonstrated no adverse effect on neutrophil and platelet recovery, or overall survival resulting from retrieval of HPC (BM and PBPC) from collection centres with transit times in excess of 24h and with some international retrievals requiring up to 90h transit times. A previous study had reported higher mortality rates and delayed platelet engraftment following HLA matched unrelated donor BM transplants facilitated by the National Marrow Donor Program with an interval of greater than 24h between collection and infusion (Lazarus et. al, Biol Blood Marrow Transplant 15: 589-596, 2009). At our centre HPC (BM and PBPC) are retrieved by trained couriers that monitor and maintain the temperature between 2 and 8oC. This is in contrast to NMDP recommendations that BM is transported at ambient temperature. Our data suggest that all HPC should be refrigerated to between 2 and 8oC and the temperature monitored during transportation. In addition, the courier should be trained to re-establish the optimal temperature for transportation if the temperature deviates from the recommended range. Disclosures: No relevant conflicts of interest to declare.

Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 227-227 ◽  
Author(s):  
Bronwen E. Shaw ◽  
Katharina Fleischhauer ◽  
Mari Malkki ◽  
Theodore Gooley ◽  
Elisabetta Zino ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Matched Pairs ◽  
Significant Difference ◽  
Unrelated Donors ◽  
Matching Criteria

Abstract Abstract 227 It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors. There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities. Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age. In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4). In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants. In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Value of Procalcitonin Arise Markedly after Use of ATG in Conditioning of HSCT without Value in Differentiating Bacterial and Non-Bacteria Inflammation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4979-4979
Author(s):  
Hui Ge ◽  
Shengli An ◽  
Chunfu Li
Keyword(s):  
Bacterial Infection ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Reactive Protein ◽  
Significant Difference ◽  
Human T Lymphocyte ◽  
Group 2 ◽  
Bacteria Culture

Abstract Background It is difficult how to differentiate bacterial infections from viral infections and to differentiate bacterial infections from other non-infective systemic inflammation. Especially in the patients with lack of neutrophil bacteria infection is usually life-threaten. The prognosis for those patients is high dependent on early diagnosis and treatment. We still feel confusing in spite of monitoring serum procalcitonin (PCT) and C-reactive protein (CRP) levels with temperature. Aim To find out whether PCT and CRP are helpful to differentiate bacterial infection and non-bacterial inflammation after use of anti-human T-lymphocyte globulin (ATG) in conditioning of hematopoietic stem cell transplantation (HSCT). Method Total 60 patients were involved in current study, who underwent HSCT and received conditioning included Cyclophosphamide, Fludarabine, ivBusufan, Thiotepa and ATG (at total dose of 5mg/kg for thymoglobulin, and 15-30mg/kg for ATG-Fresenius, respectively, on day-3 to -1). Blood samples were obtained in the morning from day-3 to 0 for testing PCT and CRP associated by daily recording temperature. Patients were grouped into Group 1 (G1, with antibiotics, n=30), Group 2 (G2, without antibiotics, n=30), Group 3 (G3, bacteria culture positive, n=7) and Group 4 (G4, bacteria culture negative, n=47) Results The value of PCT was not significant difference when G1 vs. G2 (p=0.061), and G3 vs. G4 (p=0.891), but CRP value and temperature were of significant difference between G1 and G2 (p=0.001 and 0.000, respectively). When comparing G3 with G4, CRP was significant (p=0.021) but temperature was no (0.377). However, the deference of daily CRP value was proved not to be enough to do a differential diagnosis by ROC (AUROC=0.685, 0.665, 0.643 and 0.643 on day-3 to 0, respectively). Conclusion The current study shows the value of PCT is insignificant to differentiate bacterial infection and non-bacterial inflammation after use of ATG in conditioning of HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Usefulness of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) levels in the differential diagnosis of acute bacterial, viral, and mycoplasmal respiratory tract infections in children

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Li ◽  
Lanfang Min ◽  
Xin Zhang
Keyword(s):  
Differential Diagnosis ◽  
Respiratory Tract ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Respiratory Tract Infections ◽  
Respiratory Infections ◽  
Diagnostic Value ◽  
Significant Difference ◽  
Group A ◽  
Tract Infections

Abstract Background There is a lack of studies comparing PCT, CRP and WBC levels in the differential diagnosis of acute bacterial, viral, and mycoplasmal respiratory tract infections. It is necessary to explore the correlation between above markers and different types of ARTI. Methods 108 children with confirmed bacterial infection were regarded as group A, 116 children with virus infection were regarded as group B, and 122 children with mycoplasmal infection were regarded as group C. The levels of PCT, CRP and WBC of the three groups were detected and compared. Results The levels of PCT, CRP and WBC in group A were significantly higher than those in groups B and C (p < 0.05). The positive rate of combined detection of PCT, CRP and WBC was significant higher than that of single detection. There was no significant difference in PCT, CRP and WBC levels between the group of G+ bacterial infection and G− bacterial infection (p > 0.05). ROC curve results showed that the AUC of PCT, CRP and WBC for the diagnosis of bacterial respiratory infections were 0.65, 0.55, and 0.58, respectively. Conclusions PCT, CRP and WBC can be combined as effective indicators for the identification of acute bacterial or no-bacterial infections in children. The levels of PCT and CRP have higher differential diagnostic value than that of WBC in infection, and the combined examination of the three is more valuable in clinic.

Association Between TNF and TNF Receptor II Gene Polymorphisms and Acute Graft-Versus-Host Disease in Unrelated Donor Allogeneic Haematopoietic Stem Cell Transplantation within Chinese Population.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1158-1158
Author(s):  
Haowen Xiao ◽  
Xiaoyu Lai ◽  
Gongqiang Wu ◽  
Yi Luo ◽  
Jimin Shi ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Gene Polymorphisms ◽  
Chinese Population ◽  
Conditioning Regimen ◽  
Biological Factor ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Tnf Receptor ◽  
Donor Type ◽  
Grade Ii

Abstract Abstract 1158 Poster Board I-180 Background The importance of theTumor Necrosis Factor (TNF), including TNF-αa and TNF-β, in both the initial preconditioning and effector phases of aGVHD is well established. TNF and TNF receptor II (TNFRII) gene contains multiple single nucleotide polymorphisms (SNPs) in the promoter and transcription start site. There are conflicting datas regarding the cytokines gene polymorphisms and the risk of aGVHD in several studies and no data about Chinese population. This present study was designed to test association of TNFA, TNFB and TNFRII genotype for gene polymorphisms of both donors and recipients with incidence and severity of aGVHD in HLA-matched unrelated allo-HSCT within Chinese population. Methods A total of 138 unrelated donor/recipient pairs, who had undergone HLA-matched allo-HSCT from January 2001 to March 2009 at the First Affiliated Hospital of Zhejiang University School of Medicine, were tested for TNFA (TNFαa-857 C>T,TNFαa-863 C>A,TNFαa-1031 T>C), TNFB (TNFβ+252 A>G) and TNFRII (codon 196 T>G) polymorphism allele frequencies and genotype. SNPs were analyzed by Multiplex Snapshot. Results (1) The TNFαa-857 C/C genotype of the donor or recipient was significantly associated with a higher risk of aGVHD (for donor type:75.7% vs 41.9%, P=0.001; for recipient type: 72.7% vs 50.0%, P=0.039) and a higher incidence of grade II-IV aGVHD( for donor type:50.5% vs 19.4%, P=0.002; for recipient type:48.2% vs 25.0%, P=0.033). (2) The TNFβ+252*G allele of the donor or recipient was significantly associated with a higher incidence of aGVHD (for donor type:74.5% vs 46.9%, P=0.005; for recipient type: 75.0% vs 47.1%, P=0.005); (3) The TNFRII196 T/T genotype of the donor or recipient was significantly associated with a higher incidence of aGVHD (for donor type:73.7% vs 53.8%, P=0.028; for recipient type: 73.3% vs 58.3%, P=0.086); (4) TNF and TNFRII geng polymorphic features, together with other clinical and biological factor (patient's age, donor-recipient gender, diagnosis, conditioning regimen, transplant material and GVHD prophylaxis), were subjected to multivariate analysis for aGVHD manifestation in order to exclude indirect association of gene polymorphic features. In multivariate analysis, donor-recipient gender (female to male) (RR=1.602,95%CI: 1.035-2.479, P=0.034), the TNFαa-857 C/C genotype of donor (RR=2.177, 95%CI: 1.204-3.938, P=0.01) and the TNFβ+252*G allele of recipient (RR=1.920, 95%CI: 1.116-3.304, P=0.018) were found to significantly contribute to the development of aGVHD. The TNFαa-857C/C genotype of donor (RR=3.211, 95%CI: 1.373-7.509, P=0.007) and the TNFβ+252*G allele of recipient (RR=2.174, 95%CI: 1.063-4.443, P=0.033) were also associated with a higher incidence of grade II-IV aGVHD; (5) The genotypes of TNFαa-863 and TNFαa-1031 were not found to be associated with the risk of aGVHD. Conclusions These results, which is the first report of TNF and TNF receptor polymorphic features of Chinese population with the risk of aGVHD, suggest an interaction of the donor and recipient TNFαa-857, TNFβ+252 and TNFRII196 genotypes on risk of aGVHD. These results are helpful for predict allo-HSCT outcome, identify more suitable donors and clarify therapy on an individual patient basis. Disclosures No relevant conflicts of interest to declare.

TNF-α and Its Receptors in Patients with Acute Myeloid Leukemia Undergoing alloHSCT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4484-4484
Author(s):  
Slawomira Kyrcz-Krzemien ◽  
Monika Zielinska ◽  
Agnieszka Wieclawek ◽  
Tomasz Czerw ◽  
Aleksandra Holowiecka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Serum Levels ◽  
Haematopoietic Stem Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Tnf Α ◽  
Acute Myeloid

Abstract Abstract 4484 Introduction Several studies have demonstrated, that TNF α and its receptors (sTNFR) can be used as prognostic markers for major transplant related complications (TRC) after allogeneic haematopoietic stem cell transplantation (alloHSCT). Measurement of that inflammatory cytokine and sTNFR during pretransplant conditioning and early after transplantation may also reflect the conditioning-induced tissue damage. Patients and methods Our study included a group of 36 adult patients with acute myeloid leukemia (AML) in complete remission, who underwent alloHSCT following standard myeloablative conditioning according to Bu/Cy protocol (17 patients) or reduced-toxicity myeloablative conditioning with treosulfan-based regimens (19 patients). 21 patients received alloHSCT from a sibling and 15 from an unrelated donor. The expression of TNF-α, TNFRI and TNFRII were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMC) before the start of conditioning, on the day of transplantation and on day 30 after alloHSCT. We examined β-actin as well, which constitutes an endogenous amplification control and is a housekeeping gene. sTNFRI and sTNFRII serum levels were measured using an enzyme-linked immunosorbent assay (ELISA) at the same defined time points before and after alloHSCT. The Mann-Whitney U test was used to evaluate the significance of differences between the analyzed groups and the Shapiro-Wilk and Lilliefords tests to estimate data distribution. Results TNFRII mRNA was not detected in PBMC, but TNF-α and TNFRI mRNA as well as β-actin were discovered. The real time PCR showed significant decrease (p<0.004) in TNFRI expression on day 30 after transplantation in comparison to day 0. On day 30 expression of TNFRI was higher in patients treated with Treosulfan-based regimens than in patients treated with Bu/Cy (p=0.027). Plasma levels of sTNFRI and sTNFRII observed on day 0 and 30 were significantly elevated (p<0.05) compared with the levels prior to conditioning. Conclusion Our data indicate that sTNFRI and sTNFRII can be investigated as the markers reflecting the toxicity of the conditioning regimens in AML patients undergoing alloHSCT. The associations between TNF-α, TNFRI expression, serum levels of sTNFR and the clinical outcome after alloHSCT should be evaluated. Disclosures: No relevant conflicts of interest to declare.

Contrasting the Long-Term Outcome of Reduced-Intensity Allogeneic Stem Cell Transplantation From Related Matched and Mismatched or Unrelated Matched Donor

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2029-2029
Author(s):  
Hui-Sheng Ai ◽  
Xiao-Jun Huang ◽  
Zhen-Hua Qiao ◽  
Jian-Min Wang ◽  
Ying-Min Liang ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Long Term Outcome ◽  
Hematological Diseases ◽  
Matched Group ◽  
Significant Difference ◽  
Reduced Intensity

Abstract Abstract 2029 Reduced-intensity conditioning (RIC) transplantation has been widely used in the treatment of hematological diseases. However, the comparison of long-term outcomes of RIC with HLA-matched, HLA–mismatched and unrelated donor is still lacking. Here, we reported the results of hematological patients treated at the China RIC Cooperative from the HLA-matched, HLA–mismatched and unrelated donor following to RIC. 514 patients with hematological diseases from the China RIC Cooperative Group were enrolled in this study, including 370 in HLA-matched group, 96 in HLA-mismatched group and 48 in unrelated group (table 1). The RIC conditioning regimen was based on fludarabine in combination with antilymphocyte globulin or busulfan or others. The graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, mycophenolate mofetil and methotrexat. Results showed that 505 patients achieved stable donor chimerism. The incidence of II-IV aGVHD in the HLA-mismatched group was 42.7%, significantly higher than that in the HLA-matched group (21.4%) and the unrelated group (20.8%). The 100-day transplantation-related mortality was 30.2%, 14.5% and 4.2% in the three groups, respectively. The median follow-up time was 57 months (range,7 to 141 months). The overall relapse incidence was 14.8%, including 15.7% in the HLA-matched group, 14.6% in the HLA-mismatched group and 8.3% in the unrelated group. There was no significant difference in relapse incidences in the patients with AL-CR1 and CML-CP (16.4% and 11.2%), as well between the HLA-matched group (16.9% and 16.7%) and the unrelated group (11.1% and 8.8%). For the patients with advanced leukemia, a significantly lower relapse rate was found in the HLA-mismatched group in comparison with that in the HLA-matched group (18% vs 36.2%, p<0.05, Fig. 1).The Kaplan-Meier estimated DFS and OS at 6 years for all of the 514 patients were 58.6% and 61.9% respectively, and those at 11 years were 57.8% and 61.7% respectively. The DFS and OS at 6 years in the HLA-mismatched group was 35.4% and 38.5% respectively, lower than those at 11 years in the HLA-matched group (62.7% and 67.0%, p<0.01) and those at 6 years in the unrelated group (64.6% and 66.7%, p<0.01, Figure 2 A, B). The 11-year DFS for the patients with AL-CR1, CML-CP and MDS/SAA was 68.7%, 68.5% and 73.6% respectively in the HLA-matched group. The 6-year DFS for the patients with AL-CR1, CML-CP and MDS/SAA was 55.6%, 70.7% and 62% respectively in the unrelated group, and 37.5%, 62.5% and28.6% respectively in the HLA-mismatched group. Figure 2 C,D,E£© However, the 6-year DFS in the patients with advanced leukemia was 32.0% in the HLA-matched related group, similar to that in the HLA-mismatched group (31.9%, p£¾0.05, Fig. Figure 2 F). These results indicate that RIC transplantation had similar outcome in the HLA-matched group and unrelated group but better than that from the HLA-mismatched group in haematology diseases. However, for the advanced leukemia patients, the HLA-mismatched transplantation had much lower leukemia relapse rate than in the HLA-matched group. Fig 1: The relapse rate of the patients with advanced leukemia in the HLA-mismatched group and the HLA-matched group. Disclosures: No relevant conflicts of interest to declare.

CD34+ SSCloALDHbr – a New Marker for Improved Characterization of Poor Myeloid Regeneration in the Autologous Hematopoietic Transplantation Setting?,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4007-4007
Author(s):  
Katrine Nielsen ◽  
Lea Bjerre ◽  
Hanne Oestergaard Larsen ◽  
Peter Hokland ◽  
Anne Stidsholt Roug
Keyword(s):  
Conflicts Of Interest ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Post Transplantation ◽  
Peripheral Blood Stem Cells ◽  
Platelet Recovery ◽  
Organ Systems ◽  
Cd34 Cells ◽  
Significant Difference

Abstract Abstract 4007 Background: An increasing body of evidence in different organ systems suggests that the presence of the cytosolic enzyme Aldehyde Dehydrogenase (ALDH) correlates to stemcellness. Thus, in mobilized peripheral blood stem cells (PBSCs), the side scatter low ALDH bright (SSCloALDHbr) population seems to be highly enriched for HSC as determined e.g. by Fallon et al1. However, these interesting preliminary findings need confirmation. Problem formulation: The generally accepted indirect relationship between CD34 content on the one hand, and successful hematopoietic regeneration after transplant on the other, is at least to a certain extent marred by the observation that, despite receiving sufficient weight-correlated amounts of CD34 positive HSC, some patients experience prolonged time to regeneration. Hypothesis: We hypothesized that the number of CD34+SSCloALDHbr is predictive of time to short and long-term regeneration following autologous bone marrow transplantation compared to the number of CD34+ cells alone. Results: PBSCs from 30 patients with refractory or relapsed diffuse large cell B-lymphoma referred for autologous stem cell transplantation after having failed at least three cytoreductive regimens were analyzed for ALDH expression. Laboratory results were registered on day 14 and day 100 post transplantation. Time to absolute neutrophil count (ANC) above 0,5 × 106/mL on two consecutive days was registered for each of the 30 patients. While a trend was noted for number of reinfused viable CD34+ cells (106/kg) to be correlated to ANC > 0,5 × 106/mL r=0.33, P = 0.07), only the CD34+SSCloALDHbr population correlated significantly to time to ANC > 0,5 × 106/mL (r=0.41, P =0.024). Moreover, while a positive correlation was observed between both of the analyzed subpopulations and CFU-GM proliferation, this correlation was strongest for the number of reinfused CD34+SSCloALDHbr/kg (r= 0.84, P <0.001). While neither of the analyzed subpopulations could be correlated to time to short term platelet recovery (defined as platelets > 20 × 106/mL on two consecutive days) an interesting finding emerged, when we considered day 100 platelet recoveries. Here, 11 patients were grouped as poor mobilizers (PM) having not attained a platelet count of 100 × 106/mL at day 100, and 16 patients were grouped as good mobilizers (GM) while in three cases no data were available. While mere CD34 enumeration was once more not informative, we observed a trend towards low numbers of CD34+SSCloALDHbrcells in the grafts in PM (p=0.06). With regard to long-term erythroid engraftment (defined as Hgb<100 g/L at day 100) 6 were PM (21 GM and data missing in 3) a significantly lower fraction of reinfused CD34+SSCloALDHbrwere administered to PM compared to GM (p=0.01). Once more, no significant difference in number of infused viable CD34+ cells between the groups was observed. Conclusion: In the autologous transplant setting the addition of SSCloALDHbrto standard CD34 enumeration seems to constitute a valuable marker for the identification of both time to ANC > 0,5 × 106/mL and inferior day +100 hematopoietic regeneration. While the assay does entail extra lab efforts, this layout is probably amply repaid by the possibility to institute pre-emptive therapy in PM patients. Moreover, application of the assay at the onset of leukapheresis sessions could provide a window of opportunity to administer alternative mobilization regimens, i.e. containing Plerixafor. Disclosures: No relevant conflicts of interest to declare.

Correlation Between Severity of cGvHD and Transplant Outcome: A Retrospective Monocenter Study Based on NIH Classification,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4088-4088
Author(s):  
Colombe Saillard ◽  
Roberto Crocchiolo ◽  
Sabine Furst ◽  
Jean El-Cheikh ◽  
Luca Castagna ◽  
...  
Keyword(s):  
Stem Cells ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Immunosuppressive Treatment ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Extensive Form ◽  
Hematopoietic Stem ◽  
Transplant Outcome ◽  
Significant Difference

Abstract Abstract 4088 Background: Chronic graft-versus-host disease (cGvHD) after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies is associated with lower relapse rate, due to graft-versus-tumor effect. We know that the extensive form is associated with higher transplant-related mortality after myeloablative conditioning regimen, mainly due to infectious complications as a consequence of immunosuppressive treatment. Beside the “classical” Seattle classification (limited or extensive form), a recent classification (from National Institute of Health, NIH) distinguishes three levels of severity: limited, moderate and severe. We compare here both classifications for patients receiving reduced-intensity conditioning (RIC) transplant and looked for any association of cGvHD severity with transplant outcome. Patients and Methods: We evaluated data on all adult patients with hematological lymphoid or myeloid malignancies who received HSCT from related or unrelated donor, using peripheral blood stem cells, after RIC regimens (with fludarabine-busulfan-ATG) between 1998 and 2010 at the Institut Paoli-Calmettes (Marseille, France). Data on main pre- and post-transplant variables were collected; cGvHD was classified according to its presentation and severity (with both Seattle and NIH classifications) and was correlated with overall survival (OS), non relapse mortality (NRM), and relapse. cGvHD was considered as time-dependent variable, and was included in uni- and multivariate models, after adjusting for age, disease risk, HLA compatibility, graft source and comorbidity score. Relapse or death before cGvHD was considered as a competing event. Results: 283 patients were evaluated, 121 have developed cGvHD (27 limited forms and 94 extensive forms), 162 have not, for an incidence rate of 10% and 33% of limited and extensive forms respectively. Median follow up was 607 days, patients had a median age of 50 years, transplanted for acute leukemia (55), lymphoma (78), multiple myeloma (49), myelodysplastic syndrome (24), CLL (12), CML (16) or others malignancies (19). Peripheral stem cells were mostly used (294 versus 20 bone marrow graft). We had 241 related donors and 77 unrelated donors. The median day of cGvHD occurrence was 132, we found 52 de novo forms, 40 quiescent and 26 progressive forms. After reclassification with NIH criteria, we obtained 28 mild, 52 moderate and 41 severe forms. 22 of 27 limited forms were classified as mild, the extensive forms were divided into 49 moderate and 39 severe forms. In multivariate analysis, mild and moderate forms were associated with better OS compared with other groups. Severe cGvHD was associated with significant increase in NRM. Among the other variables, only age was statistically significative in OS and NRM models. Although the incidence of relapse was lower in patients with cGvHD compared with those without, no significant difference was seen between the 3 groups of patients presenting it. Conclusion: Following a fludarabine-busulfan-ATG RIC, it seems that mild to moderate cGVHD forms are associated with better OS than patients without or with severe cGVHD. This is related to lower NRM than patients with severe cGVHD and at least a comparable antitumoral effect with respect to patients without cGVHD. This invites developing strategies limiting severity but not abrogating the effect of cGVHD. Disclosures: No relevant conflicts of interest to declare.

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