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Christopher Fegan

Publications and source records attributed to Christopher Fegan.

14 recordsLinked to original sources
PubMed2006

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.

The outcome of high-dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty-three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60-200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant-related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6-54 months) and the median time to best response was 6.5 months. Four of 17 evaluable patients (24%) became dialysis-independent at a median of 5 months post-HDT/stem cell transplantation. At a median follow-up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5-year survival in about one-third of patients.

Adult↗
PubMed2006

Two germ line polymorphisms of the tumour suppressor gene p53 may influence the biology of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is characterised by the accumulation of mature B lymphocytes. Defects in the tumour suppressor gene p53 pathway are known to be important in CLL and p53 inactivation is associated with a particularly aggressive form of CLL. A single nucleotide polymorphism (SNP) in codon 72 of TP53 leads to a single amino acid change leading to a change in apoptotic potential and alters prognosis in squamous carcinomas. A polymorphism within intron 6 of TP53 has been postulated to alter the susceptibility to lung cancer. Our study looked at the influence of these two polymorphisms in a cohort of approximately 200 CLL patients. The codon 72 polymorphism A2/A2 genotype (homozygous arginine) was associated with an increased susceptibility to CLL and CD38 negativity but did not appear to influence other biological behaviour or clinical response. The intron 6 polymorphism A2/A2 genotype was strongly associated with early stage disease, CD38 negativity and a longer time to first treatment. The effect on time to treatment did not retain significance in multivariate analysis and the polymorphism did not predict for overall survival (OS). Detailed investigation of the complete TP53 genotype is warranted to further characterise the role of SNPs in p53 and their influence on CLL.

Adult↗
PubMed2006

The P2X7 receptor gene polymorphism 1513 A-->C has no effect on clinical prognostic markers and survival in multiple myeloma.

A P2X7 receptor gene polymorphism 1513 A-->C has recently been suggested as playing a role in the pathogenesis and disease progression of chronic lymphocytic leukemia, although several studies have failed to show any effect of the polymorphism. The effects of this polymorphism were analysed in 136 patients with multiple myeloma. The frequency of the polymorphism in the myeloma samples was not significantly different from that found in normal healthy controls. There was no significant difference in age at diagnosis, creatinine, hemoglobin, beta-2 microglobulin, immunoglobulin sub-type, duration of first response and overall survival. These results are in keeping with findings in a cohort of 121 chronic lymphocytic leukemia and do not support a role for this polymorphism in multiple myeloma.

Alleles↗
PubMed2005

Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation.

Reactivation of cytomegalovirus (CMV) is a common complication following allogeneic stem cell transplantation. Genetic determinants in the host and donor that may influence the rate of reactivation are currently unknown. Viral replication is controlled by T cells and natural killer (NK) cells and these share expression of killer immunoglobulin-like receptors (KIRs). We analyzed whether activatory KIRs carried by the donor influenced the subsequent rate of CMV reactivation in the patient. In transplantations involving siblings where both donor and recipient were CMV seropositive, donors with more than one activating KIR gene were associated with a 65% reduction in CMV reactivation. Multivariate analysis confirmed a significantly reduced risk of CMV reactivation in sibling transplantations where the donor had more than one activating KIR. Reduced-intensity transplantation and graft-versus-host disease grade 2 or higher were associated with an increased risk of CMV reactivation. This observation indicates that activating KIRs play an important role in the cellular control of CMV reactivation.

Adolescent↗
PubMed2005

Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL.

The ataxia telangiectasia mutated (ATM) protein is the principal activator of the p53 protein in the response to DNA double-strand breaks. Mutations in the ATM gene have been previously found in B-cell chronic lymphocytic leukemias (B-CLLs) but their clinical significance is unknown. We analyzed 155 CLL tumors and found 12% with ATM mutations and 4% with TP53 mutations; 2 tumors contained mutations in both genes. Retrospective analysis on selected samples indicated that the ATM mutations were usually present at diagnosis. Compared with patients with wild-type ATM/TP53 genes, patients with ATM mutations had statistically significantly reduced overall and treatment-free survival. Although present in both IGVH mutation subgroups, ATM mutations were associated with unmutated IGVH genes and they provided independent prognostic information on multivariate analysis. Mutations in the ATM gene resulted in impaired in vitro DNA damage responses. Tumors with ATM mutations only partially correlated with tumors with loss of an ATM allele through an 11q deletion and, interestingly, those 11q-deleted tumors with a second wild-type ATM allele had a preserved DNA damage response. The majority of patients with ATM mutations were refractory to DNA damaging chemotherapeutic drugs and as such might benefit from therapies that bypass the ATM/p53 pathway.

Aged↗
PubMed2005

Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic Leukemia once treatment is initiated.

PURPOSE: Chronic lymphocytic leukemia (CLL) is characterized by the development of drug resistance. The underlying biologic and genetic reasons for this resistance are complex, but the bcl-2 gene family seems to play a critical role. This retrospective study assessed the clinical impact of a common single nucleotide polymorphism of the pro-apoptotic bax gene in patients with chronic lymphocytic leukemia. PATIENTS AND METHODS: The frequency of the novel polymorphism, G(-248)A, in the promoter region of the bax gene and bax protein expression was assessed in 203 CLL patients. The results were correlated with clinical outcome. RESULTS: The polymorphism was found in 23% of the CLL cohort and 15% of normal controls with no significant difference in allele frequency between the two groups (P = .15). It was associated with lower Bax protein expression and a shorter overall survival, especially in the treated patient group (P = .03). Furthermore, the adverse impact of the polymorphism was accentuated when comparing survival from the date of first treatment rather than diagnosis (P = .012). No significant difference in age at diagnosis, stage of disease at presentation, lymphocyte doubling time, time to first treatment, or progression-free survival were observed. CONCLUSION: The presence of this single nucleotide polymorphism in CLL critically influences the response to treatment and overall survival. Given the relatively high prevalence of this polymorphism in the normal population, further prospective studies in CLL and other human malignancies are indicated.

Adult↗
PubMed2005

Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival.

PURPOSE: To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. PATIENTS AND METHODS: Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 10(5) normal cells). RESULTS: Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. CONCLUSION: MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

Adult↗
PubMed2005

A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival.

B-cell chronic lymphocytic leukemia (B-CLL) is a clinically variable disease where mutations in DNA damage response genes ATM or TP53 affect the response to standard therapeutic agents. The in vitro cytotoxicity of a novel cyclin-dependent kinase inhibitor, CYC202, was evaluated in 26 B-CLLs, 11 with mutations in either the ATM or TP53 genes, and compared with that induced by ionizing radiation and fludarabine. CYC202 induced apoptosis within 24 hours of treatment in all 26 analyzed tumor samples independently of ATM and TP53 gene status, whereas 6 of 26 B-CLLs, mostly ATM mutant, showed marked in vitro resistance to fludarabine-induced apoptosis. Compared with B-CLLs, normal T and B lymphocytes treated with CYC202 displayed reduced and delayed apoptosis. Using global gene expression profiling, we found that CYC202 caused a significant down-regulation of genes involved in regulation of transcription, translation, survival, and DNA repair. Furthermore, induction of apoptosis by CYC202 was preceded by inhibition of RNA polymerase II phosphorylation, leading to down-regulation of several prosurvival proteins. We conclude that CYC202 is a potent inducer of apoptosis in B-CLL regardless of the functional status of the p53 pathway, and may be considered as a therapeutic agent to improve the outcome of resistant B-CLL tumors.

Aged↗
PubMed2003

Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses.

The ATM/p53-dependent DNA damage response pathway plays an important role in the progression of lymphoid tumors. Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease. Although the ATM and p53 pathways overlap, they are not congruent, and it is unclear how the mechanism of tumor progression differs between ATM- and p53-deficient tumors. Using microarray analysis of ATM-mutant, TP53-mutant, and ATM/TP53 wild-type B-CLLs, we show that after exposure to DNA damage transcriptional responses are entirely dependent on ATM function. The p53 proapoptotic responses comprise only a part of ATM-regulated transcription; additionally, ATM regulates prosurvival responses independently of p53. Consequently, the greater severity of the TP53-mutant B-CLLs compared with ATM-mutant B-CLLs is consistent with the additive effect of defective apoptotic and elevated survival responses after DNA damage in these tumors. We also show that transcription expression profiles of ATM-deficient, TP53-deficient, and wild-type B-CLLs are indistinguishable before irradiation. Therefore, damage-induced transcriptional fingerprinting can be used to stratify tumors according to their biologic differences and simultaneously identify potential targets for treating refractory tumors.

Apoptosis↗
PubMed2003

Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias.

The ataxia telangiectasia mutated (ATM) protein plays a central role in the cellular response to DNA double-strand breaks (DSBs). Developmentally programmed DSBs are restricted to cellular subsets within lymphoid tissues and we asked whether ATM expression is differentially regulated during lymphoid differentiation. We showed that immature B cells in bone marrow and immature T cells of the thymic cortex were negative or weakly ATM-positive. T cells of thymic medulla and peripheral tissues strongly expressed ATM. High levels of ATM were present in the B lymphocytes of the mantle zone and in plasma cells, while the majority of germinal center B cells were negative or weakly labeled. Therefore, ATM expression appears to be down-regulated at those stages of lymphoid development where physiological DNA DSBs occur. In B-chronic lymphocytic leukemia and mantle cell lymphoma we observed two categories: ATM-negative tumors, most likely reflecting the presence of ATM mutation, and tumors with abundant ATM expression. Most follicular center-cell lymphomas and diffuse large B-cell lymphomas, which rarely show inactivation of the ATM gene, were negative or weakly ATM-positive. Tumor cells from most cases of Hodgkin's disease were ATM-negative. Therefore, unless ATM inactivation occurs, ATM expression in lymphoid tumors is likely to reflect their cellular origin. As a result, immunostaining to identify lymphoid neoplasias with ATM inactivation might only be feasible for tumors derived from the stages where ATM is constitutively highly expressed.

Antibodies, Monoclonal↗
PubMed2003

T-cell depletion with Campath-1H "in the bag" for matched related allogeneic peripheral blood stem cell transplantation is associated with reduced graft-versus-host disease, rapid immune constitution and improved survival.

We studied the outcome of 24 peripheral blood stem cell (PBSC) graft recipients, who were T-cell depleted (TCD) with either 20 mg (n = 14) or 10 mg (n = 10) Campath-1H in vitro, in comparison with a retrospective cohort of 23 unmanipulated (UM) PBSC recipients. While the neutrophil engraftment was similar, the platelet engraftment occurred earlier in the TCD group (d 11 vs 14). The incidence of acute and chronic graft-versus-host-disease (GVHD) was 8.7% and 4.4% in the TCD group, respectively, compared with 47.7% and 56.3% in UM group (P < 0.001). In the TCD group, 5/6 chronic myeloid leukaemia (CML) and 4/18 non-CML patients relapsed (vs 0/6 and 3/17 in UM group, P = 0.06). All four molecular or cytogenetic relapses of CML were disease-free survivors following donor lymphocyte infusion. There was no difference in the incidence of serious infection between the TCD and UM groups and the lymphocyte recovery at 100 d was comparable. In the TCD cohort, the lymphocyte recovery was quicker in the 10 mg Campath-1H group. The non-relapse mortality (19.1%vs 66.3%) and 3 year survival (73.1 vs 19.2) were improved in the TCD group (P = 0.05). Thus elimination of late mortalities related to chronic GVHD and a rapid immune reconstitution, limiting either infection or relapse related deaths, contributed to an improved outcome following T-cell depletion with Campath-1H "in the bag".

Adult↗
PubMed2003

The P2X7 receptor gene polymorphism 1513 A-->C has no effect on clinical prognostic markers, in vitro sensitivity to fludarabine, Bcl-2 family protein expression or survival in B-cell chronic lymphocytic leukaemia.

A cohort of 121 patients with B-cell chronic lymphocytic leukaemia (B-CLL) was investigated for a single nucleotide polymorphism in the P2X7 receptor gene (1513 A-->C), and the findings were correlated with clinical prognostic markers, in vitro sensitivity to fludarabine, expression of Bcl-2 family proteins and overall survival. The frequency of the polymorphism in B-CLL samples was not significantly different from that found in normal healthy controls (P = 0.27; Fisher's exact test). Furthermore, when the B-CLL patients were analysed according to P2X7 genotype (1513 A/A versus 1513 A/C), there was no significant difference in age at diagnosis, stage at diagnosis, lymphocyte doubling time, time to first treatment, progression-free survival and overall survival, and neither was there any evidence of bias in terms of VH gene mutational status, CD38 expression, in vitro sensitivity to fludarabine or expression of Bcl-2, Bax or Mcl-1 between the two groups. These results indicate that the 1513 A-->C polymorphism of the P2X7 gene is unlikely to play a significant role in the pathogenesis or disease progression of B-CLL.

Aged↗
PubMed2002

Ataxia telangiectasia mutated-deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage.

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease involving more than one molecular mechanism that leads to the transformation of CD5(+) B cells at either the pregerminal or postgerminal center stage of differentiation. It was previously demonstrated that ataxia telangiectasia mutated (ATM) gene mutations can occur in B-CLL and cause a defect in the p53 pathway. Here the role of ATM mutations in the pathogenesis of B-CLL is addressed. Of 50 B-CLL tumors with fully analyzed ATM and TP53, 16 had ATM mutations. Six of 50 B-CLLs showed mutations in TP53 and the remaining 28 tumors had wild-type ATM or TP53. No tumor had both ATM and TP53 mutations. Remarkably, all 16 ATM mutant B-CLLs showed the absence of somatic variable region heavy chain hypermutation indicating a pregerminal center cell origin and a common pathogenesis for these tumors. Furthermore, in 5 of the 16 B-CLLs, ATM mutation preceded the transformation stage of differentiation. At the cellular level, ATM mutant tumors exhibited a deficient ATM-dependent p53 response to gamma irradiation, failure to up-regulate TRAIL-R2, a downstream target that links irradiation-induced p53 response with apoptosis, and an inability to repair induced chromosome breaks. Mantle cell lymphoma (MCL) is also of pregerminal center origin and ATM mutations are frequent in this malignancy. It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.

Adult↗