Genetic Polymorphism of Cytochrome P450 1B1 (C432G) Is Associated with An Increased Treatment-Related Mortality and Lower Overall Survival in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3287-3287
Author(s):  
Michael Koldehoff ◽  
Ahmet H. Elmaagacli ◽  
Dietrich W. Beelen
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Gene Mutation ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Cytochrome P450 1B1 ◽  
Genotype C ◽  
Type Gene ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Background. The human cytochrome P450 1B1 (CYP 1B1) is a key enzyme involved in the production of reactive metabolites and in the activation of environmental carcinogens. Several polymorphisms were identified in CYP 1B1 gene; four of them are single nucleotide polymorphisms and give rise to amino acidic substitutions. The CYP 1B1 codon 432 polymorphism leads to a three-fold higher 4-hydroxylase activity for the variant CYP 1B1 isozymes than the wild types. Never before the influence of genetic polymorphisms of CYP 1B1 (C432G) on patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT), was evaluated. Methods. Here we genotyped in a retrospective study 384 recipients (R) (and their donors (D)) for CYP 1B1 (C432G) expression that underwent allogeneic HSCT for various diseases and analyzed their outcome. Genotyping of CYP 1B1 (C432G) was performed by real-time PCR. Results. 170 R (44.3%) were genotyped as homozygous wild-type gene C/C, 157 R (40.9%) were genotyped as heterozygous genotype C/G and 57 R (14.8%) were genotype as homozygous gene mutation G/G. From the 167 D (43.5%) were C/C, 164 D (42.7%) were C/G, and 53 D (13.8%) had a homozygous gene mutation G/G. A homozygous CYP 1B1 gene mutation G/G was found on 18 R/D side (4.7%). Calculated genotype frequencies did not differ from that reported earlier by other studies for Caucasians. Five-year estimate for treatment-related mortality (TRM) and overall survival (OS) were statistically different in genotype C/G- and G/G- R with 33 ± 4%, and 49 ± 4% compared to homozygous wild-type gene C/C- R (18 ± 3%, and 59 ± 4%, respectively, [p<0.03]), whereas the five-year estimate for relapse rate (RR) was not different between the groups. No differences for five-year estimates for TRM, RR, or OS were seen in R with either genotype C/C-, C/G- or G/G- D. No statistic differences were found in the incidence of acute GVHD grade 2–4 on R- or on D- side with variant CYP 1B1 (C432G) polymorphisms. Surprisingly, the five-year estimate for TRM, RR, and OS were statistically different in homozygous gene mutation G/G on R/D site with 57 ± 2%, 81 ± 2%, and 16 ± 1% compared to all other CYP 1B1 genotypes with 28 ± 3%, 26 ± 2%, and 55 ± 3%, respectively [TRM, p<0.01; RR and OS, p<0.001]). Multivariate analysis confirmed that CYP 1B1 (C432G) homozygous gene mutation G/G on R/D site had an increased risk for TRM and RR (p<0.02), whereas the mutation G/G on R/D site revealed a worse OS (p<0.01). Conclusions. These results suggest that recipients with genetic polymorphism of CYP 1B1 do have an increased TRM, RR and lower OS after transplantation. Genotyping for CYP 1B1 (C432G) might help to identify patients with higher risk for allogeneic transplantation.

Genetic Polymorphism of NAD(P)H:Quinine Oxidoreductase 1 Is Associated with An Increased Treatment-Related Mortality in Patients Undergoing Allogeneic Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3342-3342
Author(s):  
Michael Koldehoff ◽  
Dietrich W. Beelen ◽  
Ahmet H Elmaagacli
Keyword(s):  
Genetic Polymorphism ◽  
Gene Mutation ◽  
Cellular Response ◽  
Allogeneic Transplantation ◽  
Melting Curve Analysis ◽  
Wild Type ◽  
Genotype C ◽  
Type Gene ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 3342 Poster Board III-230 Introduction: The widely expressed detoxification enzyme NAD(P)H:quinine oxidoreductase 1 (NQO1) is involved in the cellular response to oxidative stress and irradiation and protects cells against the mutagenicity from free radicals and toxic oxygen metabolities. NQO1 is subject to a genetic polymorphism (C609T) leading to a change in its amino acid sequence. Heterozygous individuals C/T have intermediate activity and homozygotes T/T are NQO1 deficient. Never before the influence of genetic polymorphisms of NQO1 on patients who underwent allogeneic transplantation, was evaluated. Methods: Here we genotyped in a retrospective study 198 patients (and their donors) for NQO1 expression that underwent allogeneic transplantation for various diseases and analyzed their outcome. Genotyping of NQO1 was performed by real-time PCR using subsequent melting curve analysis. Results: 145 patients (73.2%) were genotyped as homozygous wild-type gene C/C, 48 patients (24.2%) were genotyped as heterozygous genotype C/T and five patients (2.5%) were genotype as homozygous gene mutation T/T. From the donors 147 donors (74.2%) were C/C, 50 donors (25.3%) were C/T, and one donor (0.5%) had a homozygous gene mutation T/T. Calculated genotype frequencies did not differ from that reported earlier by other studies for Caucasians. Five-year estimate for treatment-related mortality (TRM) was highest in genotype C/T- and T/T-patients with 39% ±11% compared to homozygous wild-type gene C/C-patients (21% ± 3.9% [p<0.045]), whereas the five-year estimate for relapse or overall survival (OS) were not statistically different between the groups. No differences for five-year estimates for TRM, relapse rate, or OS were seen in recipients with either genotype C/C-, C/T- or T/T-donors. No statistic differences were found in the incidence of acute GVHD grade 2-4 within the study groups. NQO1 C/T, T/T genotypes were not associated with elevated bilirubin or creatinin levels regarding on recipient or the donor side, even after stratification based on HLA disparity. Conclusions: These results suggest that patients with genetic polymorphism of NQO1 do have an increased TRM after transplantation. Genotyping for NQO1 (C609T) might help to identify patients with higher risk for TRM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell–depleted stem cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2240-2245 ◽  
Author(s):  
Annoek E. C. Broers ◽  
Ron van der Holt ◽  
Joost W. J. van Esser ◽  
Jan-Willem Gratama ◽  
Sonja Henzen-Logmans ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Graft Versus Host ◽  
Cmv Disease ◽  
Treatment Related Mortality ◽  
Related Mortality ◽  
Acute Graft

We evaluated the efficacy, toxicity, and outcome of preemptive ganciclovir (GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients allografted between 1991 and 1996 and compared their outcome to 35 seronegative patients allografted during the same period. Both cohorts were comparable with respect to diagnosis and distribution of high- versus standard-risk patients. All patients received a stem cell graft from an HLA-identical sibling donor, and grafts were partially depleted of T cells in 109 patients. Patients were monitored for CMV antigenemia by leukocyte expression of the CMV-pp65 antigen. Fifty-two periods of CMV reactivation occurring in 30 patients were treated preemptively with GCV. A favorable response was observed in 48 of 50 periods, and only 2 patients developed CMV disease: 1 with esophagitis and 1 with pneumonia. Ten of 30 treated patients developed GCV-related neutropenia (less than 0.5 × 109/L), which was associated with a high bilirubin at the start of GCV therapy. Overall survival at 5 years was 64% in the CMV-seronegative cohort and 40% in the CMV-seropositive cohort (P = .01). Increased treatment-related mortality accounted for inferior survival. CMV seropositivity proved an independent risk factor for developing acute graft-versus-host disease, and acute graft-versus-host disease predicted for higher treatment-related mortality and worse overall survival in a time-dependent analysis. We conclude that, although CMV disease can effectively be prevented by preemptive GCV therapy, CMV seropositivity remains a strong adverse risk factor for survival following partial T-cell–depleted allogeneic stem cell transplantation.

scholarly journals Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell–depleted stem cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2240-2245 ◽  
Author(s):  
Annoek E. C. Broers ◽  
Ron van der Holt ◽  
Joost W. J. van Esser ◽  
Jan-Willem Gratama ◽  
Sonja Henzen-Logmans ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Graft Versus Host ◽  
Cmv Disease ◽  
Treatment Related Mortality ◽  
Related Mortality ◽  
Acute Graft

Abstract We evaluated the efficacy, toxicity, and outcome of preemptive ganciclovir (GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients allografted between 1991 and 1996 and compared their outcome to 35 seronegative patients allografted during the same period. Both cohorts were comparable with respect to diagnosis and distribution of high- versus standard-risk patients. All patients received a stem cell graft from an HLA-identical sibling donor, and grafts were partially depleted of T cells in 109 patients. Patients were monitored for CMV antigenemia by leukocyte expression of the CMV-pp65 antigen. Fifty-two periods of CMV reactivation occurring in 30 patients were treated preemptively with GCV. A favorable response was observed in 48 of 50 periods, and only 2 patients developed CMV disease: 1 with esophagitis and 1 with pneumonia. Ten of 30 treated patients developed GCV-related neutropenia (less than 0.5 × 109/L), which was associated with a high bilirubin at the start of GCV therapy. Overall survival at 5 years was 64% in the CMV-seronegative cohort and 40% in the CMV-seropositive cohort (P = .01). Increased treatment-related mortality accounted for inferior survival. CMV seropositivity proved an independent risk factor for developing acute graft-versus-host disease, and acute graft-versus-host disease predicted for higher treatment-related mortality and worse overall survival in a time-dependent analysis. We conclude that, although CMV disease can effectively be prevented by preemptive GCV therapy, CMV seropositivity remains a strong adverse risk factor for survival following partial T-cell–depleted allogeneic stem cell transplantation.

Human Leukocyte Antigens of A33, B58 or DR7 Decrease the Treatment-Related Mortality in HLA-Matched Sibling Hematopoietic Stem Cell Transplantation in Association with Heat Shock Protein 70-Hom Polymorphisms.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1103-1103
Author(s):  
Jin Won Kim ◽  
So Yeon Oh ◽  
Hye Jin Kim ◽  
Hyeon Gyu Yi ◽  
Kyung-Hun Lee ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Human Leukocyte ◽  
Hematopoietic Stem ◽  
Matched Sibling ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Human leukocyte antigens(HLA) are expected to influence outcomes or adverse effects in allogeneic hematopoietic stem cell transplantation through its immunologic function. However, the types of HLA and its mechanism to affect clinical outcomes are not well defined. In the other hand, heat shock protein 70-hom (HSP70-hom) plays an important role in protein folding and immune responses and was reported to influence the incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. And it was also reported that HLA types were associated with polymorphisms of HSP70-hom in several diseases. So, we evaluated the association between HLA types and HSP70-hom polymorphisms and identified the specific HLA types to affect clinical outcomes in allogeneic hematopoietic stem cell transplantation. We analyzed the DNA of patients and donors who underwent allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donors at single institute between 1998 and 2005 for malignancy or aplastic anemia. The HSP70-hom polymorphisms, rs2227956 and rs2075800, were genotyped and HLA typing was conducted in 141 patients and their donors. Individual haplotypes were estimated from genotype data of the two HSP70-hom polymorphisms using the expectation maximization algorithm. The HSP70-hom polymorphisms of patients were completely identical to those of their donors. Patients(101) with TG haplotype (TG/TA, TG/TG or TG/CG) did not only show less treatment-related mortality but also had longer overall survival compared with those(40) with non-TG haplotype (TA/TA or TA/CG). (P=0.011, P=0.013,respectively) TG haplotype was associated with HLA types of A33, B58 and DR7.(P<0.001, P=0.002, P=0.039, respectively) Patients with HLA types of A33, B58 or DR7 showed less treatment-related mortality compared with patients without the these HLA types in multivariate analyses with age, sex, transplant method, stem cell source and risk group.(P=0.034, HR=0.397, 95% CI: 0.169–0.931) In conclusion, HLA types of A33, B58 or DR7 in HLA-matched sibling hematopoietic stem cell transplantation were protective for treatment-related mortality in association with HSP70-hom polymorphisms. Figure Figure

Danapaloid Is Significantly Effective for the Prophylaxis of Hepatic Veno-Occlusive Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Study of 85 Children with Hematological Malignancies.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1122-1122
Author(s):  
Hirotoshi Sakaguchi ◽  
Sayoko Doisaki ◽  
Nao Yoshida ◽  
Hideki Muramatsu ◽  
Nobuhiro Watanabe ◽  
...  
Keyword(s):  
Risk Factor ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Hematological Malignancies ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Background: Veno-occlusive disease (VOD) is one of the regimen related toxicities in the early phase of hematopoietic stem cell transplantation (HSCT). Therapeutic modality for established VOD is limited and severe VOD cause multiple organ failure mostly with fatal prognosis despite intensive supportive care. Therefore prophylaxis of VOD is very important to reduce the treatment related mortality (TRM) after HSCT. Danapaloid, a mixture of low molecular weight heparan, dermatan, and chondroitin sulfates, promotes higher anti-coagulant activity with lower bleeding tendency than heparin could have a possibility of the prevention of VOD after HSCT. Patients: Eighty-five children with hematological malignancies (42 in CR1, CR2 or CP1 and 43 at advanced stages) underwent allogeneic HSCT from 2002 to 2008 in our institution. Underlying diseases were ALL(n=46), AML(n=26), CML(n=1), MDS(n=6), and NHL(n=6). They received bone marrow (n=69) or cord blood(n=16) from matched related (n=20), mismatched related(n=8), matched unrelated(n=30) or mismatched unrelated(n=27) donors. For the prophylaxis of VOD, dalteparin was given to 47 patients who underwent HSCT from 2002 to 2005, and danapaloid was given to 38 patients after 2005. In addition to dalteparin or danapaloid, ursodeoxycholic acid, tocopherol acetate, and eicosapentaenoic acid were given to all patients. We defined former 47 patients as dalteparin group and latter 38 patients as danapaloid group. Design: In this study, we compared the incidence of VOD, treatment related mortality at day 100 (day100 TRM) and 2 year overall survival (OS) between danaparoid group and dalteparin group as historical control in 85 consecutive patients with allogeneic HSCT. Results: In our observation, 8 patients (7 in dalteparin group, and 1 in danaparoid group) had VOD by day +30 (median day+22, range day+11 to +28) after HSCT. The probability of developing VOD for all patients was 10% (95% CI: 1–31%). Seven of 8 patients with VOD died and their probability of 2yr OS was 13% (95% CI: 1–42%). Five patients developed &gt;grade3 bleeding (4 in dalteparin group, and 1 in danapaloid group) and there was no significant difference on the probability of severe bleeding between two groups (10% versus 3%, p=0.21). In multivariate analysis by Coxhazard proportional model, the significant risk factor for the development of VOD was &gt;2nd transplant (HR: 17.5, 95%CI: 1.86–165, p=0.012) and the significant favorable factor for development of VOD was administration of danapaloid (HR: 0.09, 95%CI: 0.01–0.85, p=0.036). In the analysis of 85 consecutive HSCT procedures, the probability of day100 TRM was 15% (95% CI: 3–34%) and that of 2yr OS was 69% (95% CI: 56–78%). As for day100 TRM, the significant risk factors were &gt;2nd transplant (HR: 8.73, 95%CI: 1.75–43.5, p=0.008), HLA disparity of &gt;1Ag (HR: 10.3, 95%CI: 1.71–62.5, p=0.011) and posttransplant plasma ATIII level of &lt;96% (HR: 4.68, 95%CI: 1.05–20.8, p=0.042). As for 2yr OS, the only significant risk factor was HLA disparity of &gt;1Ag (HR: 3.26, 95%CI: 1.15–9.26, p=0.026). The danaparoid group had no significant advantage to dalteparin group on day100 TRM (HR: 0.55, 95%CI: 0.10–3.05, p=0.50) and 2yr OS (HR: 0.58, 95%CI: 0.19–1.73, p=0.33). Conclusion: Our findings suggest that administration of danapaloid is promising for the prophylaxis of VOD without increasing hemorrhagic complications. Prospective randomized, controlled study is mandatory to prove these findings.

“ATG16 L1 a Additional Risk Factor for TRM After allogeneic Stem Cell Transplantation”.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1155-1155
Author(s):  
Karin Landfried ◽  
Martin Hausmann ◽  
Gerhard Rogler ◽  
Daniel Wolff ◽  
Anne M Dickinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Innate Immunity ◽  
Risk Factor ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Genetic Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 1155 Poster Board I-177 Introduction A genome wide association scan of DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16 L1 as a new genetic risk factor of Crohn's disease. As our group had previously reported SNPs of another innate immunity receptor important in Crohn's disease, NOD2/CARD15, as a risk factor of severe graft-versus-host disease (GvHD) and treatment related mortality (TRM) following allogeneic stem cell transplantation (SCT), we now assessed the role of ATG16L in complications following SCT. Material and Methods A total of 127 HLAidentical sibling donor/recipient pairs were included. DNA from donors and recipients were analyzed for the ATG16L1 polymorphism and presence or absence of NOD2/CARD15 variants as previously published. Results of ATG16L1 and NOD2/CARD15 were correlated with clinical characteristics and outcome data, which were documented in a SPSS 17 database. The role of polymorphisms in GvHD III/IV was assessed by cross tabs, treatment related mortality (TRM) and overall survival were assessed by Kaplan Meier analysis. All patients and donors gave informed consent to analysis of genetic risk factors of GvHD. Results In 15 (12%) both recipient and donor were wildtype ATG16L1, in 25 (19%) either donor or recipient had the variant; and in 87 (69%) both donor and recipient had the variant. In 34 pairs, additional NOD2/CARD15 SNPs were observed. Severe GvHD occured in 6%, if both donor and recipient were ATG16L1 wildtype but increased to 22% if donor or recipient had the variant. Treatment related mortality increased in the presence of a donor variant (16% versus 46%, p 0.03) or if both; recipient and donor had variants (21% vs 48%, p 0.03). There seemed to be a gene dose effect for TRM, which was 13% if both were wildtype, 27% in the presence of either a donor or recipeint varaint and 48% if both had the variant (p≤ 0.05). Overall survival was not significantly different between these groups. In multivariate analysis, presence of ATG16L1 variant in both, donor and recipient was an independent risk factor for treatment related mortality when compared with age and stage of underlying disease (Hazard ratio 2.5, 95% confidence interval 1.1 – 6.1). Additional presence of NOD2/CARD15 variants seemed to be additive: TRM rose from 36% in recipients with ATG16L1 variant to 59% in the presence of additional recipient NOD2/CARD15 variants and from 34% in donors with ATG16L1 variants to 64%, if donors had additional NOD2/CARD15 SNPs. Conclusions As reported ATG16L1 polymorphism is a genetic risk factor for inflammatory bowel disease. In our work ATG16L1 polymorphism seems also to contribute to increased TRM in patients receiving allogeneic SCT. An accurate analysis of the causes of death is still accomplished. Altogether the data underline the role of the innate immunity and the disturbed antibacterial defense in the pathophysiology of transplant-associated complications. Disclosures No relevant conflicts of interest to declare.

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