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Biomedical subjects

K S Peggs

Publications and source records attributed to K S Peggs.

15 recordsLinked to original sources
PubMed2006

Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans.

Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment modality for a number of hematologic malignancies, as well as inherited immunodeficiencies and hemoglobinopathies, and may also have a role in selected acquired autoimmune disorders. The complete or near-complete ablation of host immunity and subsequent establishment of donor-derived immunity that is required for successful engraftment and long-term outcomes provide a major obstacle to such transplantation approaches. A delicate balance exists between the need for the reconstituted donor-derived immunity to provide both protection against pathogenic challenges and graft-versus-malignancy activity, and the potentially harmful expansion of alloreactive T-cell clones mediating GvHD. The search for interventions that would allow more rapid and selective reconstitution of beneficial immune specificities continues to be informed by the development of new tools enabling a more precise dissection of the kinetics of reconstituting populations. This review summarizes more recent data on immune reconstitution following allogeneic transplantation in humans.

Graft vs Host Disease↗
PubMed2005

The effect of low-dose aciclovir on reactivation of varicella zoster virus after allogeneic haemopoietic stem cell transplantation.

Patients undergoing haemopoietic stem cell transplants (HSCT) are at high risk of varicella zoster virus (VZV) reactivation, with a significant incidence of dissemination. This study reports a retrospective analysis of 247 allogeneic HSCT recipients receiving anti-viral prophylaxis with low-dose oral aciclovir 400 mg/day, administered until immunosuppression was discontinued and the CD4(+) cell count exceeded 200/mm(3). Viral reactivation was successfully suppressed by aciclovir prophylaxis, with only one case of breakthrough infection. The cumulative incidence of zoster infection at 1 year post transplant was 2% and at 5 years 34%. In all, 64 patients discontinued prophylaxis. Zoster developed in 26 of these, giving a cumulative incidence of infection at 1 year after stopping aciclovir of 39% and at 3 years 44%. Infection occurred in a localised dermatomal distribution in 93% of cases. This supports previous findings that aciclovir prophylaxis prevents early VZV reactivation, although the long-term incidence is not affected as infection occurs once prophylaxis is discontinued. Such infection, however, is mild and localised. This study does not support the idea that use of such low-dose aciclovir regimens reduces the zoster incidence by permitting subclinical reactivation during prophylaxis, and therefore the re-establishment of protective anti-viral immunity.

Acyclovir↗
PubMed2005

Use of 18F-FDG positron emission tomography following allogeneic transplantation to guide adoptive immunotherapy with donor lymphocyte infusions.

Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) provides valuable prognostic information in the management of lymphoma patients. However, the utility of (18)F-FDG PET following allografting is unclear. We analysed the use of (18)F-FDG PET after allogeneic reduced-intensity transplantation (RIT) performed in our institution. Between June 1998 and January 2002, 55 patients underwent RIT for either Hodgkin or non-Hodgkin lymphoma. At least one (18)F-FDG PET scan was performed during the post-transplant period (median five studies) in 15 (27.2%) of these 55 patients. PET scans were performed after re-staging computed tomography (CT) and were categorised depending on (18)F-FDG uptake. The first PET scan was informative in 11 of 15 patients (73%) and influenced the administration of donor lymphocyte infusions (DLI) in nine: leading to earlier DLI administration in two patients, earlier dose escalation in one, withholding of DLI administration in five and dose reduction in one. In addition, subsequent monitoring with (18)F-FDG PET scans documented a graft-versus-lymphoma effect in five patients (median post-DLI follow-up 33 months, range 13-36 months). These preliminary data suggest that (18)F-FDG PET has a role in guiding DLI administration and monitoring the immunotherapeutic effect in patients after allogeneic transplantation. This retrospective pilot study forms the basis for a prospective study to clarify the utility of (18)F-FDG PET/CT in these patients.

Adult↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2002

Development and evaluation of an internally controlled semiautomated PCR assay for quantification of cell-free cytomegalovirus.

Quantification of circulating human cytomegalovirus (HCMV) is useful in clinical contexts such as virological surveillance of bone marrow transplant recipients and monitoring of antiviral therapy. This report describes an internally controlled, quantitative, semiautomated, HCMV genome assay that was developed primarily to measure HCMV DNA in the plasma of severely leucopaenic patients. It exhibits greater sensitivity, wider dynamic range and higher sample throughput than a number of previously described commercial and "in-house" assays. Viral DNA extraction from EDTA plasma samples was automated using a BioRobot 9604 (Qiagen). HCMV strain AD169 was used to prepare a calibration curve and murine cytomegalovirus (MCMV) strain Smith was added as internal control to all calibration standards and test samples. Amplification was performed using a set of primers based on the HCMV UL50 region, capable of amplifying both human and murine CMV. The yield of biotinylated polymerase chain reaction (PCR) products was estimated using HCMV-specific and MCMV-specific enzyme-labelled probes and automated chemiluminescence detection. Log-transformed HCMV-to-MCMV signal ratios were calculated and used for quantification of test samples against simultaneously extracted MCMV-spiked calibration standards. Evaluation of the assay sensitivity by Probit analysis demonstrated a 95% probability of detection at 100 HCMV genomes per ml of plasma; the dynamic range was shown to be > or = 4 log(10). A total of 315 samples from 61 bone marrow transplant patients were analysed by both the quantitative PCR (qPCR) and by a previously validated nested nonquantitative PCR (NQPCR). A high level of concordance (90%) was observed between the two assays, although the qPCR assay exhibited slightly greater sensitivity.

Base Sequence↗
PubMed2002

Peripheral blood stem cell transplantation for POEMS syndrome.

In common with other plasma cell dyscrasias in which a small tumour burden is associated with severe clinical symptoms (notably systemic AL amyloidosis) the possible benefits of dose intensification are yet to be fully explored in POEMS syndrome. One important issue is whether the toxicity of the procedure is significantly increased in this group. We report two cases of POEMS syndrome with solitary asymptomatic bone lesions treated with high-dose melphalan (200 mg/m(2)) and peripheral blood stem cell (PBSC) rescue. In both cases there was minimal peri-transplant morbidity and a subsequent substantial and maintained improvement in the peripheral neuropathy.

Adult↗
PubMed2002

Clinical trials with CMV-specific T cells.

BACKGROUND: Reactivation of latent CMV following allogeneic hematopoietic stem cell transplantation remains a major cause of morbidity despite improvements in surveillance protocols and antiviral drug therapies. Selective restoration of anti-CMV cellular immunity is an attractive alternative approach if it can be achieved in a non-toxic manner that can be widely utilized. The application of CMV-specific adoptive cellular therapies following the initial proof of principle provided almost a decade ago has been limited be a number of factors including the practical difficulties of exporting technically demanding and labor-intensive methodology to smaller transplant centers. METHODS: We review the lessons learnt from studies in the setting of EBV-associated post transplant lymphoproliferative disease and the advances in both understanding and technology that have allowed the development of a multitude of new approaches for the generation of CMV-specific T cells suitable for adoptive transfer. These include the use of monoclytes, dendritic cells and B-lymphoblastoid cell lines as the presenting cells of antigen delivered by pulsing with exogenous proteins or peptides, or of antigen processed endogenously following transduction with one of a variety of viral vectors. We also discuss some of the issues surrounding the planning and implementation of trial protocols incorporating these products, and the techniques necessary for monitoring the fate of the infused cells and their efficacy. Finally, we review the preliminary data that is available on the newer generation of clinical trials that are ongoing in this field. DISCUSSION: Extensive characterization of many different systems used to culture CMV-specific cells has now been performed. These suggest that it is now possible to generate T cells with specificity for a number of different CMV-specific target antigens (most commonly the lower matrix protein pp65). Clinical trials using these products within the current regulatory guidelines ares till in their infancy. However, preliminary results are beginning to suggest that the newer generation of CMV-specific T cell products can be administered with a relatively low risk of graft-versus-host disease, and that antiviral activity can be demonstrated following infusion.

Adoptive Transfer↗
PubMed2001

Exploiting graft-versus-tumour responses using donor leukocyte infusions.

Allogeneic stem cell transplantation (SCT) has become the treatment of choice for some patients with haematological malignancies, allowing dose escalation of chemo-radiotherapy beyond the limits imposed by bone marrow toxicity. However, it is now apparent that dose escalation alone does not eradicate the malignancy in many cases and that an associated immune-mediated graft-versus-malignancy effect may be equally important. Its presence is supported by the following observations: anecdotal reports that patients with relapsed leukaemia following SCT may re-enter remission after withdrawal of immunosuppressive drugs; the lower risk of relapse associated with the development of graft-versus-host-disease (GVHD); and an increased risk of relapse in patients receiving syngeneic transplants or T-cell depleted allogeneic marrow grafts. More directly compelling evidence has been provided by the efficacy of donor lymphocyte infusions, particularly for relapsed chronic-phase CML. Issues that remain to be resolved include the precise nature of the effector cells and their target antigens, the best strategies for separating graft-versus-malignancy from GVHD, the role of adjuvant chemotherapy/cytokines, and the role of non-myeloablative transplantation.

Antigens, Neoplasm↗
PubMed2001

Cellular therapy: donor lymphocyte infusion.

The dose escalation of chemoradiotherapy that is achievable with stem cell transplantation is often insufficient to eradicate malignancy, and an associated immune-mediated graft-versus-malignancy effect may be equally important for many diseases. The most directly compelling evidence for its presence is the efficacy of donor lymphocyte infusions in generating anti-tumor responses, particularly for relapsed chronic-phase chronic myeloid leukemia. Response rates and durability appear lower with myeloma and acute myeloid leukemia and myelodysplasia syndrome, and minimal with acute lymphoblastic leukemia. There is relatively little data on indolent lymphoid malignancies. Issues that remain to be resolved include the precise nature of the effector cells and their target antigens, the best strategies for separating graft-versus-malignancy from graft-versus-host disease (GVHD) and their effect on the durability of responses, and the role of adjuvant chemotherapy/cytokines. Similar issues surround routine combination with nonmyeloablative transplantation protocols and preliminary data suggests that GVHD may continue to provide a major obstacle.

Graft vs Host Disease↗
PubMed2000

Extended routine polymerase chain reaction surveillance and pre-emptive antiviral therapy for cytomegalovirus after allogeneic transplantation.

Pre-emptive treatment strategies based on sensitive screening for cytomegalovirus (CMV) infection up to day +100 after allogeneic transplantation have been shown to reduce the incidence of CMV disease during the period of surveillance. However, the use of ganciclovir has been associated with delays in immune reconstitution and an increased incidence of late CMV disease after day +100. In the present study, 81 patients undergoing allogeneic transplantation received polymerase chain reaction (PCR)-guided pre-emptive therapy based on detection of CMV DNA by PCR on 2 consecutive weeks up to day +180. Thirty-three of the 52 high-risk patients (CMV-seropositive donor or recipient) received a total of 45 treatment episodes up to day +100. Three of these patients (5.7%) developed CMV disease, with one fatality. Twelve of the surviving 44 high-risk patients (27%) required pre-emptive treatment between days +101 and +192, but none of these patients developed late CMV disease with a median follow-up of 402 d (range 117-952 d). Antiviral therapy was stopped after a single negative PCR result with no subsequent episodes of CMV disease while patients remained off antiviral treatment. As all initial episodes of CMV DNA detection occurred within 60 d of transplantation, it may be possible to discontinue monitoring beyond day +100 in patients who have remained CMV PCR negative before this. Thus, we have confirmed that PCR-guided pre-emptive therapy results in a low incidence of CMV disease before day +100 and that discontinuing treatment on the basis of viral clearance as determined by CMV PCR appears to be safe practice. In addition, we have observed no episodes of late CMV disease with an extension of surveillance to 26 weeks.

Acyclovir↗