CTLA-4 Polymorphisms and Haplotype Correlate with Survival and aGVHD after Allogeneic Stem Cell Transplantation from Related HLA-Haplotype-Mismatched Donor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2006-2006
Author(s):  
Xiao-Ying Qin ◽  
Yu Wang ◽  
Guo-Xuan Li ◽  
Yazhen Qin ◽  
Lan-Ping Xu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conflict Of Interest ◽  
Conflicts Of Interest ◽  
Immunosuppressive Agents ◽  
Negative Regulator ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Mismatched Donor

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure.T cell homeostasis is critical to determine the potency of the GVT effect. Cytotoxic T lymphocyte antigen-4 (CTLA-4 or CD152) is a T cell activation negative regulator. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT. Patients and Methods: In this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 154 acute leukemia patients after related HLA-haplotype-mismatched transplantation. The four SNP genotypes (-1661, -318, CT60 and +49) were determined by TaqMan SNP genotyping assays. Results: Recipients of donors with +49 GG showed significantly lower OS (69.1% vs. 85.6%, P=0.024) and higher incidence of III-IV aGVHD (10.0% vs. 2.1%, P=0.032) than those with GA + AA(Fig.1,Fig.2). Multivariate analyses showed that +49GG was an independent risk factor for OS (HR:0.457,95%CI=0.227-0.920,P=0.028). Patients receiving mDLI showed significantly lower OS with +49 GG donor than those with AG+AA (P=0.011).The haplotype analysis revealed only three haplotypes in the donor population -1661/-318/CT60/+49 i.e.,ACGG,ACAA and GTGA,the frequencies were 64.3%, 19.5%, and 16.2%, respectively.Donors with and without the ACGG/ACGG haplotype had the same effect on transplant outcome as those with +49 GG and +49 AG+AA. Conclusion: The CTLA-4 +49 GG and the haplotype ACGG/ACGG reduced the overall survival and increased the aGVHD after allo-HSCT from the related HLA-haplotype-mismatched donor,knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for donor selection and individual application of immunosuppressive agents and immunotherapy. CONFLICT OF INTEREST The authors declare no conflict of interest. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Impact of Allogeneic Hematopoietic Stem Cell Transplantation on Kidney Function in Children—A Single Center Experience

2021 ◽  
Vol 10 (5) ◽  
pp. 1113
Author(s):  
Kinga Musiał ◽  
Krzysztof Kałwak ◽  
Danuta Zwolińska
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Serum Creatinine ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Kidney Function ◽  
Hematopoietic Stem ◽  
Oncological Patients ◽  
The Impact

Background: Knowledge about the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on renal function in children is still limited. Objectives: The aim of the study was to evaluate kidney function in children undergoing alloHSCT, with special focus on differences between patients transplanted due to oncological and non-oncological indications. Materials and Methods: The data of 135 children undergoing alloHSCT were analyzed retrospectively. The serum creatinine and estimated glomerular filtration rate (eGFR) values were estimated before transplantation at 24 h; 1, 2, 3, 4 and 8 weeks; and 3 and 6 months after alloHSCT. Then, acute kidney injury (AKI) incidence was assessed. Results: Oncological children presented with higher eGFR values and more frequent hyperfiltration rates than non-oncological children before alloHSCT and until the 4th week after transplantation. The eGFR levels rose significantly after alloHSCT, returned to pre-transplant records after 2–3 weeks, and decreased gradually until the 6th month. AKI incidence was comparable in oncological and non-oncological patients. Conclusions: Children undergoing alloHSCT due to oncological and non-oncological reasons demonstrate the same risk of AKI, but oncological patients may be more prone to sustained renal injury. Serum creatinine and eGFR seem to be insufficient tools to assess kidney function in the early post-alloHSCT period, when hyperfiltration prevails, yet they reveal significant differences in long-term observation.

The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2003-2008 ◽  
Author(s):  
Michael Boeckh ◽  
W. Garrett Nichols
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cohort Studies ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Preemptive Therapy ◽  
Prevention Strategies ◽  
Hematopoietic Stem ◽  
The Impact

AbstractIn the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell–depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.

The impact of cytokine gene polymorphisms on the outcome of HLA matched sibling hematopoietic stem cell transplantation

Cytokine ◽  
2018 ◽  
Vol 110 ◽  
pp. 404-411 ◽  
Author(s):  
Azza M. Kamel ◽  
Abdallah Gameel ◽  
Gamal T.A. Ebid ◽  
Eman R. Radwan ◽  
Mostafa F. Mohammed Saleh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Gene Polymorphisms ◽  
Cytokine Gene ◽  
Hematopoietic Stem ◽  
Matched Sibling ◽  
Cytokine Gene Polymorphisms ◽  
The Impact

Phase I Study of Ipilimumab (Neutralizing Monoclonal Anti-CTLA4 Antibody) To Treat Relapse of Malignancy after Allogeneic Hematopoietic Stem Cell Transplantation: Evidence of Tumor Regression without Induction of GVHD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 410-410
Author(s):  
Asad Bashey ◽  
Bridget Medina ◽  
Sue Corringham ◽  
Mildred Pasek ◽  
Ewa Carrier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Negative Regulator ◽  
Hematopoietic Stem ◽  
Anti Cancer ◽  
Grade 3

Abstract Failure of adoptive cellular immunotherapy is an important cause of relapse of malignancy (RM) and death following allogeneic hematopoietic stem cell transplantation (allo-HCT). CTLA-4 is a negative regulator of activated T-cells. Therapeutic blockade of CTLA-4 has demonstrated potent anti-cancer effects in animal models, and in patients with some solid tumors. Although CTLA-4 blockade may augment graft-versus-malignancy following allo-HCT, GVHD and other immune complications may also be increased. We report the results of a completed phase I dose-escalation trial of a neutralizing human monoclonal anti-CTLA-4 antibody (ipilimumab) in patients with RM following allo-HCT. Eligibility criteria included allo-HCT ≥90 days previously, > 50% donor T-cell chimerism, no prior grade 3/4 GVHD, no prophylaxis/therapy for GVHD for ≥ 6 weeks. Patients received a single dose of ipilimumab over 90 min. (Donor lymphocyte infusion (DLI) at a dose of 5 x 10e6 CD3 cells/kg was allowed 8 weeks following ipilimumab if no GVHD occurred and malignancy was present. Seventeen patients (13M, 4F; median age 42 (21–64); Hodgkin’s disease [HD] =7 Myeloma [MM]=3, CML=2, CLL=1, AML=1, NHL=1, Renal Ca =1, Breast Ca=1; 14 related donors, 3 unrelated; 5 myeloablative, 12 RICT) were treated at three centers (4 at dose-level 1 [DL1] 0.1 mg/kg, 3 at 0.33 mg/kg [DL2], 4 at 0.66 mg/kg [DL3], 3 at 1.0 mg/kg [DL4] and 3 at 3.0 mg/kg [DL5]). Six patients had failed prior DLI. Median time between BMT and ipilimumab was 374 d (125–2368). Seven patients received additional DLI. Ipilimumab was well tolerated in this setting. No DLT was seen at levels up to DL5. No infusional toxicity was seen. No patient developed clinically significant GVHD within 90 days following ipilimumab. One patient developed grade II acute GVHD of the skin 12 weeks following DLI. Two possible immune breakthrough events were documented: grade 3 polyarthropathy 14 weeks following ipilimumab, but also 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, DL1, RhF+ pre- ipilimumab); grade 1 chemical hyperthyroidism with thyroid-stimulating antibody 6 weeks post ipilimumab (CLL, DL3). Two patients developed objective evidence of disease response after ipilimumab alone: regression of refractory lymphadenopathy in a patient with mantle cell NHL lasting 3m [DL4]; CR in a patient with HD ongoing at 2m [DL5].Both patients had failed prior DLI. Two additional patients demonstrated possible anti-cancer effects (reduction of PB and BM blasts in AML, DL1; maintenance of molecular remission in a CML patient given ipilimumab alone for 2.5 yrs despite stopping imatinib, DL1). PK data will be presented. This study shows that clinically active doses of ipilimumab (up to 3.0 mg/kg) can safely be administered to patients with RM following allo-HCT without inducing/exacerbating GVHD. Organ specific immune breakthrough events can be seen as in non-allo-HCT patients.

Assessment of Individual Characteristics on the Pharmacokinetics of Oral Busulfan in Adults Patients Undergoing Hematopoietic Stem-Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1993-1993
Author(s):  
Philippe Bouchard ◽  
Sarah Bilodeau ◽  
Karine Alain ◽  
Barbara Vadnais ◽  
Martin Franco ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Volume Of Distribution ◽  
Individual Characteristics ◽  
Oral Clearance ◽  
Hematopoietic Stem ◽  
Hepatic Transaminase ◽  
The Impact

Abstract Introduction Busulfan is one of the most commonly used drugs in preparative regimens for hematopoietic stem-cell transplantation. Administration of accurate doses of busulfan is critical to limit toxicity while ensuring maximum efficacy. Indeed, busulfan pharmacokinetics exhibit important interpatient variability and its therapeutic interval is narrow. Objective To determine the impact of glutathione-S-transferase (GST) genotype and individual characteristics on the pharmacokinetics of oral busulfan in adult patients. Methods An observational retrospective study was performed. Individual characteristics were obtained from the medical charts of adult patients who received oral busulfan between June 2003 and May 2007. Genotype for the enzyme GST A1 was determined in patients for whom consent was available. Linear regression analysis was used to identify the variables that have significant impact on oral clearance of the first dose of busulfan. Oral and intravenous pharmacokinetics were also compared in patients presenting between November 2006 and May 2007. Results Oral clearance on the first dose of busulfan was available for 104 of the 106 eligible patients. Lean body weight (LBW) was used to determine the dose and was a significant predictor of oral clearance (r = 0,61; r2 = 0,37). No added precision was obtained with the addition of age, bilirubin and hepatic transaminase levels (r = 0,62; r2 = 0,38). GST genotype was determined for 87 patients and an increase in precision is obtained when adding GST genotype to LBW for prediction of oral clearance (r = 0,65; r2 = 0,43). The impact of GST genotype was found to be independent of all other variables considered. The model that includes LBW, GST genotype, age, bilirubin and hepatic transaminase levels provides little further precision (r = 0,67; r2 = 0,45). No significant impact was identified when considering the following variables: gender, creatinine clearance, albumin, lactate deshydrogenase and alkaline phosphatase levels, prior history of chemotherapy and/or radiotherapy, concomitant use of acetaminophen or antifungal drugs. The impact of GST genotype (*A wild-type allele, *B variant allele with reduced activity) on oral clearance was also evaluated. A significant difference in busulfan clearance between individuals with the *A/*A genotype and individuals with the *B/*B genotype was observed (p = 0,003; ANOVA and Bonferroni). In the prospective study, eight patients agreed to receive their second dose of busulfan via the intravenous route. Oral clearance was a good estimation of absolute clearance (Student’s t-test for mean difference p = 0,573; r = 0,963). Volume of distribution of busulfan was an excellent predictor of oral clearance for the 8 patients (r = 0,96; r2 = 0,93) and LBW was an adequate predictor of volume of distribution (r = 0,94; r2 = 0,88). Conclusion An increase in precision could be obtained by adjusting the busulfan dose with LBW and GST genotype rather than LBW alone. No other individual patient characteristic was identified that influences significantly the pharmacokinetics of oral busulfan. More than 50% of intersubject variability in busulfan oral pharmacokinetics remains unexplained even after considering all above variables. Estimation of volume of distribution may represent a very innovative and promising avenue to more closely predict busulfan dosage.

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