title: Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation.
abstract: Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P=0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P=0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P=0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P<0.0005) and CD8 (P<0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab.
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK [3] Section of Haemato-Oncology, Royal Marsden Hospital, Surrey, UK.
authors.forename: B E
authors.initials: BE
authors.lastname: Shaw
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Lee
authors.affiliation: Department of Haematology, Northampton General Hospital, Cliftonville, Northampton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Krishnamurthy
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Byrne
authors.affiliation: Academic Haematology, Nottingham University Hospitals, Nottingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Seedhouse
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: N P
authors.initials: NP
authors.lastname: Mayor
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Maldonado-Torres
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Saudemont
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: S G E
authors.initials: SG
authors.lastname: Marsh
authors.affiliation: 1] Anthony Nolan Research Institute, Royal Free Hospital, London, UK [2] UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Madrigal
authors.affiliation: 1] Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, UK [2] Academic Haematology, Nottingham University Hospitals, Nottingham, UK.
authors.forename: N H
authors.initials: NH
authors.lastname: Russell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D064591:Allografts; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes; D019172:Transplantation Conditioning / Q000009:adverse effects*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074323:Alemtuzumab; C505530:CASP8 protein, human; D053181:Caspase 8