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Biomedical subjects

A J Barrett

Publications and source records attributed to A J Barrett.

At least 19 recordsLinked to original sources
PubMed2006

Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents.

The realization in the 1990s that allogeneic stem cell transplants (SCT) have a potentially curative graft-versus-leukemia (GVL) effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning (RIC) regimens, aimed primarily at securing engraftment to provide the GVL effect, while minimizing regimen-related toxicity. It is now over 10 years since RIC regimens were heralded as a new direction in the field of SCT. Over the last decade much has been learned about the ways in which the conditioning regimen can be tailored to provide adequate immunosuppression, and modulated to deliver a chosen degree of antimalignant treatment. The huge literature of clinical data with RIC transplantation now permits us to more clearly define the success and limitations of the approach. This review examines the origins of RIC SCT, explores the degree to which the initial expectations and purpose of the approach have been realized, and outlines some ways forward for the field.

Graft vs Leukemia Effect↗
PubMed2006

Health-related quality of life in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.

Reduced-intensity conditioning allogeneic HSCT (RIC) has less regimen-related morbidity and mortality than myeloablative allogeneic HSCT (MT) offering allogeneic transplantation to patients otherwise excluded. Whether these advantages improve health-related quality of life (HRQL) is unknown. We examined the HRQL effects of RIC and MT in patients with hematological diseases pre-transplant (baseline), days 0, 30, 100, 1 and 2 years following HSCT. HRQL was measured using the Short Form-36 Health Survey and the Functional Assessment of Cancer Therapy - General and BMT. Data were analyzed using mixed linear modeling adjusting for baseline HRQL differences. Patients (RIC=41, MT=35) were predominately male (67%), in remission/stable disease (65%) with an Eastern Cooperative Oncology Group status <or=1 (97%). HRQL progressively improved (P<0.01) in both groups with higher scores at day 100 compared to days 0 and 30; there was no difference between groups during early recovery. At 2 years, all survivors (n=43) reported HRQL similar or better than baseline. Results suggest RIC and MT patients experience a similar pattern of HRQL improvement during early recovery. Two-year survivors report a return to baseline or better in HRQL by day 100, with the exception of physical health in MT patients.

Adult↗
PubMed2006

Accurate diagnosis of acute graft-versus-host disease using serum proteomic pattern analysis.

OBJECTIVE: The rapid diagnosis of acute graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) is important for optimizing the management of this life-threatening complication. Current diagnostic techniques are time-consuming and require invasive tissue sampling. We investigated serum protein pattern analysis using surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass spectrometry as a tool to diagnose GVHD. PATIENTS AND METHODS: Eighty-eight serum samples were obtained from 34 patients undergoing HCT either pretransplant (n = 28 samples) or at various time points posttransplant (n = 60 samples), including 22 samples obtained on the day of onset of acute GVHD symptoms. Serum proteomic spectra generated from a "training set" of known samples were used to identify distinct proteomic patterns that best categorized a sample as either pretransplant, posttransplant non-GVHD, or GVHD; these distinct proteomic signatures were subsequently used to classify samples from a masked "test" sample set into the appropriate diagnostic category. RESULTS: Proteomic pattern analysis accurately distinguished GVHD samples from both posttransplant non-GVHD samples and pretransplant samples (100% specificity and 100% sensitivity in both cases). Furthermore, distinct serum proteomic signatures were identified that distinguished pretransplant from posttransplant non-GVHD samples (100% specificity and 94% sensitivity). CONCLUSION: These preliminary data suggest a potential application of SELDI-TOF-based proteomic analysis as a rapid and accurate method to diagnose acute GVHD.

Adult↗
PubMed2006

A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis.

Systemic mastocytosis (SM) is a disease characterized by tissue infiltration of neoplastic mast cells originating from hematopoietic stem cells. Patients with advanced SM have a poor prognosis, and there is no mast cell ablative therapy available for most patients who carry an activating point mutation in the c-kit gene. We report results of a prospective study evaluating the safety, engraftment, and possibility of inducing a graft-versus-mast cell (GvMC) effect after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) from an HLA-identical sibling. Three patients with advanced SM were transplanted. All achieved complete donor T cell chimerism followed by clinical evidence for GvMC effect. However, all patients experienced disease progression with the longest response duration of 39 months. The GvMC effect can be observed after nonmyeloablative HCT with limited efficacy. Effective cytoreductive therapy prior to HCT may be required for long-term disease control and cure.

Adult↗
PubMed2005

Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation.

Donor lymphocyte infusions (DLI) have been the mainstay of treatment for chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (allo-SCT). Imatinib mesylate (IM) is also effective in these patients. However, advanced phase relapse (APRel) responds poorly with either treatment. To test the possibility that combinations of DLI and IM might be more effective, 37 patients with CML relapsing after allo-SCT between August 1994 and May 2004 were studied. Ten had molecular relapse (MRel), 14 hematological relapse (HRel) and 13 APRel. Thirteen received DLI, 9 IM and 11 DLI+IM. Four patients received DLI+IM but not concurrently. Thirty (81%) patients responded (actuarial survival and current leukemia-free survival of 80.6 +/- 6.7% and 69.1 +/- 7.7%). Of 30 patients, 26 are in molecular remission (MR), median follow-up of 1,226 days (range 249-3257) since relapse. Ten of 11 patients (including four with APRel) treated with DLI+IM achieved MR in 3 months and all are alive in MR. In contrast, only two of 22 treated with either modality (1/13 DLI and 1/9 IM) achieved MR at 3 months, 15 are alive, 11 in MR. Four patients receiving nonconcurrent DLI+IM are also alive in MR. In conclusion, DLI appears to synergize with IM to induce rapid and durable MR.

Adolescent↗
PubMed2005

Phenotype and function of a CD56+ peripheral blood monocyte.

G-CSF primed CD34 cells cultured for 2-3 weeks in IL-2 and stem cell factor generate CD56(high) cells with phenotypic and morphologic features of NK cells, and a novel adherent CD56(low) CD16- population expressing myeloid markers (CD33 and HLA-DR). We hypothesized that similar cells might also occur in peripheral blood. In 13/13 normal individuals, we found a circulating population of CD56(low), CD33+, FcgammaRI+, FcgammaRII+, HLA-DR+, CD11b(high), CD14+ monocytes closely resembling the cultured CD56(low)CD33+ cells. They may represent a normal counterpart of the CD56+ CD33+ hybrid myeloid/natural killer cell leukemia. Their mean frequency was 1.3+/-1% (standard deviation), range 0.16-3.5%, of total mononuclear cells. CD56(low)CD33+ cells, primed with cytomegalovirus antigen, induced autologous T-lymphocyte proliferation comparably to CD56-, CD14+ peripheral blood monocytes (PBM). Conversely, CD56(low) cells induced greater T-cell proliferation than CD56- PBM when lymphocyte responders were HLA mismatched. Unstimulated CD56(low)CD33+ cells showed a low antiproliferative effect on K562, which was increased upon LPS stimulation. The pattern of cytokine production by CD56(low)CD33+ cells and PBM largely overlapped; however, they produced detectable levels of IL-6 and IL-1beta. These results define a minor monocyte population with distinct phenotypic and functional features.

CD56 Antigen↗
PubMed2005

Selective depletion strategies in allogeneic stem cell transplantation.

Despite improved prophylaxis and treatment, GvHD remains a major limitation to optimal allogeneic stem cell transplantation. Ex vivo selective depletion (SD) is a strategy to prevent GvHD, in which host-reactive donor lymphocytes are selectively eliminated from a PBSC allograft while useful donor immune function is preserved. The elimination of alloreactive and thereby GvHD-mediating T cells has been shown to be feasible in both pre-clinical and more recently clinical studies. However, SD techniques and the translational research needed for clinical application are still under development. Here we summarize and discuss the following aspects of the SD approach: selection of an appropriate allogeneic stimulator; the responder population; the alloresponse; methods for removal of alloreacting T cells; product testing; clinical considerations. Our review highlights the diversity of possible approaches and the need to develop different techniques for specific clinical applications.

Clinical Trials as Topic↗
PubMed2004

Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease.

A retrospective chart review was performed on seven patients treated with topical ocular corticosteroid therapy for progressive cicatricial conjunctivitis associated with chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. A clinical grading criteria for conjunctival GVHD based on the degree of cicatrization was developed and patients graded prior to therapy. During the treatment course, the dose and frequency of topical corticosteroids and clinical outcomes were recorded. A complete response was defined as a complete resolution of the conjunctival hyperemia with either total resolution of the conjunctival fibrovascularization or presence of inactive conjunctival scarring. Prednisolone acetate 1% eye drops were used in a total of eight courses of therapy in seven patients. A complete response was documented in all seven patients with a total treatment duration of 7 weeks (median, range: 3-16 weeks). Additional studies are required to determine the long-term safety and efficacy of topical corticosteroids for cicatricial conjunctivitis associated with ocular GVHD in the context of a randomized, prospective clinical trial.

Adolescent↗
PubMed2004

Loading DCs with Ag.

Understanding the biology of the DC and its pivotal role in immune response initiation and regulation has enabled new effective anti-cancer therapies to be developed for treatment of a wide range of tumor types. Many studies on DC-based cancer vaccine development have focused on the development of methods that can effectively deliver tumor Ags to DCs. Numerous methods have been developed or evaluated for the delivery of defined and undefined tumor Ags to DCs for processing and presentation to T lymphocytes. This review provides a brief summary of these methods, the techniques that are used in each, how they have -- or could -- be applied clinically, as well as the advantages and disadvantages of each method.

Adoptive Transfer↗
PubMed2004

Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis.

Approximately 15% of patients undergoing non-myeloablative allogeneic haematopoietical cell transplantation (NMHCT) develop steroid-refractory acute-graft versus host disease (aGVHD), a usually fatal complication. We encountered 18 cases of steroid-refractory aGVHD in 146 patients, undergoing NMHCT from a related human leucocyte antigen-compatible donor following cyclophosphamide/fludarabine-based conditioning. Our initial cohort of steroid-refractory aGVHD patients treated with antithymocyte globulin (ATG) and mycophenolate mofetil (regimen-1: n = 6) had high GVHD-related mortality. Therefore, we investigated an alternative strategy for subsequent patients developing this complication (regimen-2: n = 12), consisting of daclizumab (alone or combined with infliximab/ATG) and targeted broad spectrum antibacterial and aspergillus prophylaxis in conjunction with rapid tapering of steroids to minimize opportunistic infections. In a retrospective analysis, patients receiving regimen-2 were significantly more likely to have complete resolution of GVHD compared with those receiving regimen-1 [12/12 (100%) vs. 1/6 (17%); P < 0.001]. When compared with those receiving regimen-1, regimen-2 patients also had a higher probability of survival at day 100 (100% vs. 50%) and day 200 (73% vs. 17%) post-transplant, and improved overall survival (median 453 d vs. 42 d from aGVHD onset; P < 0.0001). GVHD-related mortality was 89% for regimen-1 patients vs. 17% for regimen-2 patients (P < 0.0001). These data suggest that a co-ordinated approach using immunoregulatory monoclonal antibodies, pre-emptive antimicrobial therapy and judicious steroid withdrawal can dramatically improve outcome in steroid-refractory aGVHD.

Adolescent↗
PubMed2003

Allogeneic hematopoietic stem cell transplantation for myeloproliferative disorders and myelodysplastic syndromes.

Allogeneic SCT is the most effective method to achieve cure in patients with MPD and MDS. This approach is associated with significant risk of morbidity (eg, GVHD) and TRM, although the incidence and severity vary based on donor and recipient characteristics. For young patients with HLA-matched donors, SCT is the preferred therapy. Efforts to improve outcome for older patients and for patients with alternative donors have led to decreased treatment-associated complications with associated better long-term DFS.

Humans↗
PubMed2003

Cyclosporine is required to prevent severe acute GVHD following T-cell-depleted peripheral blood stem cell transplantation.

Reduced immunosuppression may improve immune recovery and increase the graft-versus-leukemia effect after allogeneic stem cell transplantation. Furthermore, the requirement for post-transplant immunosuppression following extensive T-cell depletion remains unclear. We therefore evaluated the role of cyclosporine (CSA) in recipients of HLA-identical T-cell-depleted peripheral blood stem cell transplants (PBSCT), followed by donor lymphocyte infusions (DLIs) scheduled on days +45 and +100. Before day+45, successive cohorts of patients received decreasing amounts of CSA: standard-dose (SD) CSA, low-dose (LD) CSA, or no CSA until day+45. LD CSA was as effective as SD CSA in preventing acute graft-versus-host disease (GVHD). However, moderate-to-severe acute GVHD was significantly more frequent before the day +45 DLI in patients receiving no CSA (33.3 vs 12.7%, P=0.036, including the only four grade III-IV cases). As a result of higher rates of early acute GVHD, more patients in the 'no CSA' group failed to receive any DLI (30.7 vs 7.1%, P=0.01). Overall, there was no difference in the incidence of acute GVHD, as patients receiving CSA developed more GVHD after DLI. Similarly, no significant differences were found in chronic GVHD, transplant-related mortality, or survival. These results define a role for CSA in preventing GVHD at low T-cell doses following PBSCT.

Acute Disease↗
PubMed2003

Tissue-restricted T cell alloresponses across HLA barriers: selection and identification of leukemia-restricted CTL in HLA-mismatched stimulator-responder pairs.

Exploiting the graft-versus-leukemia (GVL) effect in mismatched transplants requires its separation from graft-versus-host disease (GVHD). We generated leukemia-specific cytotoxic T lymphocytes (CTL) in three haplotype-mismatched, two class I-mismatched and two single HLA-A locus-matched stimulator-responder pairs. Six patients with chronic myelogenous leukemia and one patient with acute myeloid leukemia transformed from MDS were studied. CTL generated after 10 days stimulation with unselected leukemic peripheral blood mononuclear cells inhibited leukemic CFU-GM colony growth (>85% at 10:1 effector:target ratio) with no third-party colony inhibition. In five pairs, responders were cultured separately with leukemia cells, PHA-B or LCL from the stimulator. After 2-4 restimulations, the T cell repertoire was examined by flow analysis using Vbeta-specific antibodies. Test cultures (but not controls) showed preferential expansion of 1-4 Vbeta families either common to two or more stimulators or unique to a particular stimulator. Notably, we elicited leukemia-specific TCR Vbeta expansions on four out of five occasions. In two pairs, responder cells selected for the appropriate leukemia-specific Vbeta family were shown to have leukemia-specific cytotoxicity. These leukemia-restricted T-cells were CD8+ or CD4+ and CD25+ or CD57+. The results support the development of strategies to selectively deplete GVHD and conserve GVL reactivity in mismatched transplants.

Bone Marrow Transplantation↗
PubMed2003

The graft-versus-leukemia effect of nonmyeloablative stem cell allografts may not be sufficient to cure chronic myelogenous leukemia.

We treated 12 patients with chronic myelogenous leukemia (CML) with a low-intensity preparative regimen followed by allogeneic stem cell transplantation in an attempt to confer a curative graft-versus-leukemia (GVL) effect with minimum morbidity. Seven patients in first chronic phase (CP1) and five in second chronic phase (CP2) (age 15-68 years) received a nonmyeloablative conditioning regimen of fludarabine and cyclophosphamide, followed by a G-CSF-mobilized peripheral blood stem cell (PBSC) transplant from an HLA-identical sibling. Cyclosporine (CsA) was used for graft-versus-host disease (GVHD) prophylaxis. Median follow-up was 384 days. Neutrophil recovery occurred at a median of 12 days. There was no transplant-related mortality. Of the seven CP1 patients transplanted, seven achieved a stable molecular remission; two with no post-transplant intervention, three after donor lymphocytes, imatinib and interferon, and two after a myeloablative stem cell transplant. Four of five CP2 patients died in blast crisis and one survived in molecular remission. Of the 12 patients with durable engraftment, six had Grades II-IV acute GVHD; six had limited chronic GVHD. These results suggest that cytoreduction is required to optimize the curative effect of allogeneic stem cell transplantation for CML.

Adolescent↗
PubMed2002

Immune-globulin prophylaxis of respiratory syncytial virus infection in patients undergoing stem-cell transplantation.

Thirty-two patients undergoing allogeneic hematopoietic stem-cell transplantation were given respiratory syncytial virus (RSV) immune globulin (RSVIG) at the time of transplantation and again 3 weeks later. Antibody titers to RSV, human parainfluenza virus 3, measles, and influenza H1N1, H3N2, and B were measured prior to administration of RSVIG and 6 more times over the course of the subsequent 6 weeks. Baseline antiviral titers and increases in antibody after administration of RSVIG were extremely variable for all the viruses. In 18 patients in whom the baseline titers of antibody titers to RSV-F protein were 1:640-1:2048, there was a 7.7-fold initial increase in these titers after the first dose of RSVIG, compared with a 2.1-fold increase in 14 patients with baseline titers of 1:4096-1:20,840; increases in titers of antibody against the other viruses after the first dose of RSVIG reflected similar variability. The subset of patients with the lowest titers appear to receive the greatest benefit from administration of RSVIG.

Antibodies, Viral↗