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S Mackinnon

Publications and source records attributed to S Mackinnon.

At least 19 recordsLinked to original sources
PubMed2006

Role of allogeneic transplantation in low-grade lymphoma and chronic lymphocytic leukemia.

PURPOSE OF REVIEW: Indolent lymphoproliferative disorders are incurable with conventional chemotherapy. Exploring the potential of allogeneic transplantation to eradicate disease has therefore been of interest for some time. This review reports on recent developments in this field to evaluate the current status of stem cell transplantation in the management of these conditions. RECENT FINDINGS: Most recent studies examine the application of reduced intensity regimens in follicular non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Interest is particularly focused on assessing the potency of the allogeneic graft-versus-malignancy effect, whether achieved by T cells infused at the time of transplant, or by the administration of exogenous donor lymphocytes at relapse or progression following transplant. Furthermore, the discovery of molecular/genetic factors that permit identification of patients with poor prognosis chronic lymphocytic leukemia has led to interest in identifying whether the allogeneic effect can overcome the impact of these factors. SUMMARY: Encouraging evidence is accumulating for the efficacy of reduced intensity transplantation in indolent lymphoproliferative disorders. Allogeneic graft-versus-malignancy effects can be demonstrated and durable responses to donor lymphocytes are being reported. More follow-up is required, however, before the curative potential of allogeneic transplantation can be assessed. The appropriate timing of transplant and the choice of regimen remains unclear.

Biomarkers, Tumor↗
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

Outbreaks of infectious diseases in stem cell transplant units: a silent cause of death for patients and transplant programmes.

Following the closure of the National Blood and Bone Marrow Transplant Unit in Dublin, because of an outbreak of vancomycin-resistant enterococcal infection, a survey was carried out by the EBMT to investigate the occurrence of outbreaks of infection in SCT units and the impact on patient morbidity, mortality and the administration of the transplant programme over a 10-year period from 1991 to 2001. A total of 13 centres reported 23 outbreaks of infection involving 231 patients: 10 bacterial, eight viral and five fungal outbreaks were reported and 56 deaths were attributed to infection. All fungal and bacterial deaths and the majority of viral deaths occurred in allograft recipients. In all outbreaks, the infection was reported to be hospital acquired and in all the viral, and half the bacterial infections, cross-infection was a major factor. All viral, four of 10 bacterial and three of five fungal outbreaks occurred in HEPA filtered rooms. A total of 12 SCT units reported a partial or total closure. The introduction of mandatory quality management systems such as JACIE should result in a change in attitude to 'incident reporting' and together with future surveys should reduce the incidence of infectious outbreaks in SCT units.

Aspergillosis↗
PubMed2004

Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation.

We report the incidence, characteristics and outcome of neurological complications occurring following reduced-intensity conditioning (RIC) in 85 patients who received a related/unrelated donor stem cell transplantation following therapy with alemtuzumab, fludarabine and melphalan. Six patients (probability 8.9%) developed severe neurological complications at a median of 151 days (24-334 days). Five of them presented with progressive peripheral sensori-motor radiculo-neuropathy and/or myelitis, preceded by one or more viral reactivation/infection. Despite treatment with immunoglobulins/plasmapheresis/steroids, four died of respiratory failure due to progressive peripheral neurophathy. Viral infection was identified as the only risk factor for the development of neurological complications. Patients who are treated with alemtuzumab-based RIC may have a lower risk of developing regimen-related neurological complications, but are more susceptible to develop peripheral radiculo-neuropathy or myelitis. This phenomenon may be possibly related to viral infection associated with delayed immunological recovery or immunological dysregulation caused by alemtuzumab-induced T-cell depletion.

Adolescent↗
PubMed2003

Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies.

Most bone marrow transplant recipients are infertile due to reversible or irreversible testicular failure. However, little is known about the gonadotoxic potential of the newly introduced nonmyeloablative transplants. We undertook a 24-month longitudinal study in a cohort of 32 recipients of nonmyeloablative transplantation to test whether the combined regimen of fludarabine, melphalan and CAMPATH-1H can induce damage to germ cell (GC) and Leydig cell (LC) compartments. Testicular function was assessed immediately prior to transplantation and at four time points post-transplant to compare hormonal levels before and after the procedure. Two other groups treated with BEAM- and TBI-related regimes were also included in the study group for comparative purposes. GC function was assessed by measuring basal serum follicle stimulating hormone (FSH). LC function was assessed by measuring basal luteinising hormone (LH) and testosterone (T) levels. LC reserve was assessed by measuring the T/LH ratio. As a group, patients who received a non myeloablative transplant sustained severe damage to the GC compartment, as evident from a substantial elevation in the FSH level post-transplant (12 IU/l vs 18.4 IU/l, P<0.001). Similar to the GC injury, patients as a group sustained significant damage to the LC compartment following the transplant (5.4 IU/l vs 9.6 IU/l, P<0.001). In general, patients had reduced LC reserve post-BMT, as evident from a diminished T/LH ratio (2.6 pretransplant vs 1.6 post-transplant P=0.05). Patients who received a nonmyeloablative transplant had a similar effect on the GC and LC compartments compared to those who had a BEAM autograft. On the other hand, patients who received a TBI-based transplant sustained more damage to their GC and LC compartments compared to those who received a nonmyeloblative transplant; however, this was not statistically significant (P=0.09). Our data suggest that this type of regimen is potentially gonadotoxic and consideration should be given to fertility counselling and testosterone replacement therapy post-transplant.

Adult↗
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

Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of nonmyeloablative conditioning?

The anti-CD52 (Campath-1) monoclonal antibodies (Mabs) have a substantial history of use for controlling graft-versus-host disease in allogeneic bone marrow transplantation. Now, with the availability of a humanised form, alemtuzumab (Campath-1H), and the demonstration that this agent can reduce the tumour burden in B-CLL, a new niche may be found - as a potentially curative agent in which its tumour purging ability in vivo combines with its role as a conditioning agent in nonmyeloablative transplantation. Review of the literature shows that alemtuzumab has unique advantages as a method of depleting malignant lymphocytes, including those in patients resistant to conventional chemotherapy. Alemtuzumab can also be used in BMT for depletion of normal T and B lymphocytes of both the recipient and donor for prevention of graft rejection and GVHD. It allows good stem cell recovery with resultant rapid engraftment, has a low risk of EBV-triggered secondary malignancy and does not interfere with blood stem cell mobilisation. As a method of eliminating the malignant clone in B-CLL, alemtuzumab has shown remarkable efficacy in heavily pre-treated patients, a number of whom have progressed to autologous or allogeneic transplantation. Efficacy data are shown within the context of other transplantation data for B-CLL. These results indicate that the combination of tumour-depleting and immunosuppressive properties of alemtuzumab should be explored, with the hope of providing improved treatment options for elderly patients with advanced B-CLL or indolent lymphoma whose prognosis is too poor currently to allow treatment with traditional regimens of high-dose myeloablative chemotherapy.

Adult↗
PubMed2002

Human herpesvirus-7 infection of the CNS with acute myelitis in an adult bone marrow recipient.

The beta-herpesviruses, human herpesviruses-6 and -7 (HHV-6 and HHV-7), are closely related and have very similar biological behaviour. While HHV-6 is associated with encephalitis in immunosuppressed adults, HHV-7 is not recognised as a cause of neurological disease in such patients. This report describes the identification of a reactivated HHV-7 infection in the cerebrospinal fluid of an adult who presented with an acute myelitis 11 months after unrelated donor bone marrow transplant.

Anti-Inflammatory Agents↗
PubMed2002

Transcription-mediated amplification and hybridisation protection assay to determine BCR-ABL transcript levels in patients with chronic myeloid leukaemia.

Detection of BCR-ABL transcripts in chronic myeloid leukaemia (CML) is used to confirm the diagnosis and to monitor residual disease. Quantitative techniques are required to predict response to therapy or early relapse. We have evaluated an assay in which transcription-mediated amplification (TMA) of BCR-ABL and ABL transcripts is achieved using reverse transcriptase and RNA polymerase. The products are quantified in the hybridisation protection assay (HPA) using acridinium ester-labelled DNA probes and chemiluminescence. The method is a single tube procedure which uses small amounts of RNA (<500 ng/triplicate analysis), is technically simple (requiring just two waterbaths and a luminometer), rapid (total assay time <4 h) and sensitive (capable of detecting one BCR-ABL-positive K562 cell in the presence of 10(4)-10(5) BCR-ABL-negative cells). BCR-ABL signals from patient RNA samples were quantified relative to known amounts of K562 RNA and normalised to levels of ABL. BCR-ABL/ABL ratios ranged from 0.15 to 1.59 (median 0.65) in RNA from diagnostic blood or bone marrow of 18 CML patients and were < or =0.0001 in 20 normal controls. Sequential samples analysed from six CML patients post-allogeneic bone marrow transplantation who relapsed and received donor lymphocyte infusions showed BCR-ABL/ABL ratios which reflected patient status or treatment. A BCR-ABL/ABL ratio of 0.01 served as a useful arbitrary indicator value, with results above and below this value generally correlating with relapse or remission, respectively.

Acridines↗
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

Induction of cytomegalovirus (CMV)-specific T-cell responses using dendritic cells pulsed with CMV antigen: a novel culture system free of live CMV virions.

Recipients of allogeneic transplants are at risk of cytomegalovirus (CMV) infection and disease during the period of immune compromise after transplantation. The limitations of current antiviral pharmacotherapy have led to attempts to develop alternative strategies for preventing or treating CMV infection, such as adoptive transfer of donor-derived virus-specific T cells. Methods for generating CMV-specific T cells either use live CMV to infect autologous antigen-presenting cells (APCs) or require some knowledge of the immunodominant peptides involved in the immune response. A novel culture system was developed that does not use live virions and in which the APCs are monocyte-derived dendritic cells (DCs). APCs were pulsed with CMV antigen and cocultured with autologous peripheral blood lymphocytes from donors seropositive for CMV. The culture-output cells consisted of both CD4- and CD8-expressing T cells. Proliferation, as determined by a tritium-thymidine-incorporation assay, showed significant CMV-antigen specificity in cultures from 15 of 15 donors seropositive for CMV. In cytotoxicity assays, cytotoxic T lymphocytes from 10 of 12 cocultures specifically lysed autologous CMV-infected fibroblasts or DCs but not HLA-mismatched or uninfected target cells, and this activity was shown to be blocked by HLA class 1 blocking antibodies. T-cell-receptor spectratyping of cells from the cultures typically showed complex size-distribution patterns, with all size classes of a normal preculture distribution present. However, a few size-class peaks were expanded compared with the preculture patterns and these may have represented expansions of CMV-specific T-cell clones. Advantages of this culture system are that it requires no live virions and no detailed knowledge of the antigenic peptides involved and it is applicable to CMV-seropositive donors of any HLA type.

Antibodies, Viral↗