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R Champlin

Publications and source records attributed to R Champlin.

At least 19 recordsLinked to original sources
PubMed2006

Steroid myopathy in patients with acute graft-versus-host disease treated with high-dose steroid therapy.

High-dose steroids are the first line of treatment for acute graft-versus-host disease (aGVHD). Steroid myopathy is a debilitating steroid-induced complication that significantly impairs a patient's performance status. To determine the frequency and severity of steroid myopathy and other steroid related complications in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) who developed grade >or=2 aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT), we performed a retrospective analysis. Patients were included in the analysis if they had a diagnosis of AML/MDS, underwent an allogeneic HSCT between January 1996 and December 2001 and developed grade >or=2 aGVHD that was treated with 2 mg/kg of methylprednisolone and survived at least 100 days post transplant. A total of 70 patients fulfilled our inclusion criteria. Steroid myopathy was identified in 29 (41%) patients. Steroid myopathy was generally of moderate severity with severe debilitating steroid myopathy seen in only 3% of patients. We concluded that steroid myopathy is a common complication of high-dose steroid therapy after allogeneic HSCT in AML/MDS. Interventions aimed at preventing and treating this complication are warranted and need to be explored in prospective clinical trials.

Acute Disease↗
PubMed2006

Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells.

One factor limiting the therapeutic efficacy of cord blood (CB) hematopoietic progenitor cell (HPC) transplantation is the low cell dose of the graft. This is associated with an increased incidence of delayed or failed engraftment. Cell dose can be increased and the efficacy of CB transplantation potentially improved, by ex vivo CB expansion before transplantation. Two ex vivo CB expansion techniques were compared: (1) CD133+ selection followed by ex vivo liquid culture and (2) co-culture of unmanipulated CB with bone-marrow-derived mesenchymal stem cells (MSCs). Ex vivo culture was performed in medium supplemented with granulocyte colony-stimulating factor, stem cell factor and either thrombopoietin or megakaryocyte growth and differentiation factor. Expansion was followed by measuring total nucleated cell (TNC), CD133+ and CD34+ cell, colony-forming unit and cobblestone area-forming cell output. When compared to liquid culture, CB-MSC co-culture (i) required less cell manipulation resulting in less initial HPC loss and (ii) markedly improved TNC and HPC output. CB-MSC co-culture therefore holds promise for improving engraftment kinetics in CB transplant recipients.

AC133 Antigen↗
PubMed2006

Ex vivo expanded umbilical cord blood T cells maintain naive phenotype and TCR diversity.

BACKGROUND: Umbilical cord blood (CB) is a promising source of hematopoietic stem cells for allogeneic transplantation. However, delayed engraftment and impaired immune reconstitution remain major limitations. Enrichment of donor grafts with CB T cells expanded ex vivo might facilitate improved T-cell immune reconstitution post-transplant. We hypothesized that CB T cells could be expanded using paramagnetic microbeads covalently linked to anti-CD3 and anti-CD28 Ab. METHODS: CB units were divided into three fractions: (1) cells cultured without beads, (2) cells cultured with beads and (3) cells cultured with beads following CD3+ magnetic enrichment. All fractions were cultured for 14 days in the presence of IL-2 (200 IU/mL). RESULTS: A mean 100-fold expansion (range 49-154) of total nucleated cells was observed in the CD3+ magnetically enriched fraction. Following expansion, CB T cells retained a naive and/or central memory phenotype and contained a polyclonal TCR diversity demonstrated by spectratyping. DISCUSSION: Our data provide evidence that naive and diverse CB T cells may be expanded ex vivo and warrant additional studies in the setting of human CB transplantation.

Antigens, CD↗
PubMed2005

Umbilical cord blood-derived cells for tissue repair.

Hematopoietic tissue-derived cells, including stem cells, have been shown to generate solid organ tissue-specific cells. Besides bone marrow and peripheral blood, umbilical cord blood (UCB) has the advantage of being an easily accessible stem cell source provided as a banked cell product. Using the xenogeneic human into NOD/SCID mouse stem cell transplant model preliminary data suggest UCB-derived tissue-specific cells generated in liver, pancreas, CNS and endothelium. In a clinical sex-mismatched UCB transplant setting Y-positive, UCB-derived gastrointestinal epithelial cells and CNS-specific cells have been identified in female patients. The potential therapeutic use of UCB cells for tissue repair is, however, limited by a low total stem cell number available and by HLA-disparity.

Animals↗
PubMed2005

Ex vivo expansion of umbilical cord blood.

The efficacy of cord blood (CB) transplantation is limited by the low cell dose available. Low cell doses at transplant are correlated with delayed engraftment, prolonged neutropenia and thrombocytopenia and elevated risk of graft failure. To potentially improve the efficacy of CB transplantation, approaches have been taken to increase the cell dose available. One approach is the transplantation of multiple cord units, another the use of ex vivo expansion. Evidence for a functional and phenotypic heterogeneity exists within the HSC population and one concern associated with ex vivo expansion is that the expansion of lower 'quality' hematopoietic progenitor cells (HPC) occurs at the expense of higher 'quality' HPC, thereby impacting the reserve of the graft. There is evidence that this is a valid concern while other evidence suggests that higher quality HPC are preserved and not exhausted. Currently, ex vivo expansion processes include: (1) liquid expansion: CD34+ or CD133+ cells are selected and cultured in medium containing factors targeting the proliferation and self-renewal of primitive hematopoietic progenitors; (2) co-culture expansion: unmanipulated CB cells are cultured with stromal components of the hematopoietic microenvironment, specifically mesenchymal stem cells (MSC), in medium containing growth factors; and (3) continuous perfusion: CB HPC are cultured with growth factors in 'bioreactors' rather than in static cultures. These approaches are discussed. Ultimately, the goal of ex vivo expansion is to increase the available dose of the CB cells responsible for successful engraftment, thereby reducing the time to engraftment and reducing the risk of graft failure.

Cell Culture Techniques↗
PubMed2005

Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.

Adult↗
PubMed2004

Outcomes of autologous stem cell transplantation in patients with multiple myeloma who received dexamethasone-based nonmyelosuppressive induction therapy.

High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves survival in myeloma (MM). The role of induction therapy on outcomes of ASCT in MM has not been systematically studied. Nonmyelosuppressive (NMS) steroid-based induction can be used in MM, with the potential of reducing neutropenias and other toxic effects prior to ASCT. NMS induction however could be associated with poorer outcomes if disease control or stem cell collection were inadequate. We studied outcomes of 136 MM patients who underwent HDC and ASCT as part of their initial therapy between March 1998 and December 2000. Of these, 46 received HDC and ASCT without any exposure to myelosuppressive agents, 39 received myelosuppressive therapy for disease control and/or stem cell collection, and 51 received alkylating agent-based initial treatment. We compared OS and EFS rates, stem cell collectability, and contamination of the grafts with monoclonal plasma cells. After a median of 33 months, response rates, EFS and OS rates were comparable in the three groups of patients. Adequacy of stem cell collection and plasma cell contamination were similar. Our data support the hypothesis that NMS induction for patients with MM is safe and effective and does not compromise the results of HDC.

Dexamethasone↗
PubMed2004

CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study.

A CD8 murine monoclonal antibody-coated high-density microparticle (HDM) has been developed, which allows for the rapid depletion of CD8+ T cells from apheresis products by gravity sedimentation. We conducted a study to determine the efficacy and safety of CD8 depletion of donor lymphocyte infusions (DLI) to treat relapse after stem cell transplantation using the Eligix CD8-HDM Cell Separation System. Patients were targeted to receive 3 x 10(7) CD4+ T cells/kg. Nine patients were enrolled, three with CML, three myeloma, two CLL, and one NHL. A median of 1 x 10(10) mononuclear cells were obtained by apheresis and processed. The median depletion of CD8+ cells was 99.3% (97.8->99.5%). CD8 depletion was highly specific, with a median recovery of CD4+ cells of 75%. A median of 2.9 x 10(7) CD4+ cells/kg was infused. No infusional toxicity was noted. All CML patients achieved a complete molecular remission. A CLL patient demonstrated a complete response. One patient developed GVHD (grade II acute GVHD and subsequently chronic GVHD). The CD8-HDM Cell Separation System appears to be highly selective and effective in depleting CD8+ T cells from DLI apheresis products, and CD8-depleted DLI is capable of mediating a graft-versus-leukemia effect while minimizing GVHD.

Adult↗
PubMed2004

Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma.

Clinical outcomes were evaluated in 89 consecutive patients with multiple myeloma that had not responded to dexamethasone-based primary therapy, who received early intensive therapy supported by autologous stem cell transplantation. Results were compared with those of 45 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the response rate was 69% including 16% with CR. Survival of 14 patients with CR (median >7.0 years) was significantly longer than those of 47 patients with PR (median 4.5 years) or of 28 patients who remained NR (median 2.2 years). CR occurred in 43% of patients with serum myeloma protein <1.5 gm/dl, in contrast to 7% of those with higher values, a finding similar to that observed previously for patients consolidated in PR. No prognostic factor was associated with PR and, in view of the high frequencies of PR or CR, all patients with primary resistant myeloma should be considered for early intensive therapy. The limited improvement of lifespan and disease-free survival for those in PR indicated the need for further treatment to achieve CR, the major surrogate marker for long survival.

Adult↗
PubMed2003

Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results.

We conducted a retrospective analysis of all allogeneic stem cell transplantation (ASCT) patients started on extracorporeal photopheresis (ECP) for the management of steroid-dependent (SD) or steroid-refractory (SR) cutaneous chronic graft-versus-host disease (cGVHD) following ASCT during a 36-month period (9/98-8/01). Only SD or SR patients who were treated by ECP after day 100 and who received at least 4 weeks of ECP were considered evaluable for this analysis. Out of 64 ASCT patients reviewed, 32 patients met the inclusion criteria. All 32 patients had been previously treated with systemic corticosteroids with 11 (34%) being SR and 21 (66%) SD. Cutaneous cGVHD was extensive in 28 patients (88%) and was accompanied by visceral (hepatic, gastrointestinal) cGVHD in 23 patients (72%). The 32 evaluated patients had received a median of three prior therapies before ECP, most commonly systemic corticosteroids, tacrolimus, and mycophenolate mofetil. Patients received a median of 36 ECP sessions (range 12-98) over a median of 5.3 months (range 1-28), with a median of six sessions per month. The complete response (CR) rate was 22% (n=7) and the partial response rate was 34% (n=11). In all, 28 patients were on systemic corticosteroid therapy at ECP initiation and 18 patients achieved 50% dose reduction while on ECP, yielding a 64% steroid-sparing response rate. Of seven CRs, five are ongoing. A total of 11 (34%) patients have died after ECP, with all cases due to visceral cGVHD or cGVHD-related infectious complications. All 21 surviving patients remain on at least some immunosuppressive cGVHD therapy (including ECP in eight). Overall, ECP displays a substantial response rate and, in particular, steroid-sparing activity in SR/SD extensive cutaneous cGVHD. However, most patients continue to require at least some chronic therapy and cGVHD-related morbidity and mortality remain high.

Adolescent↗
PubMed2003

Adult stem cells and tissue repair.

Recently, adult stem cells originating from bone marrow or peripheral blood have been suggested to contribute to repair and genesis of cells specific for liver, cardiac and skeletal muscle, gut, and brain tissue. The mechanism involved has been termed transdifferentiation, although other explanations including cell fusion have been postulated. Using adult stem cells to generate or repair solid organ tissue obviates the immunologic, ethical, and teratogenic issues that accompany embryonic stem cells.

Adult↗
PubMed2002

Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma.

The purpose of the study was to determine the feasibility and efficacy of a reduced intensity conditioning regimen of fludarabine and melphalan for allogeneic transplantation in patients with multiple myeloma. From August 1996 to December 2000, 22 patients received a reduced intensity conditioning regimen with fludarabine and melphalan. Median age was 51 years (range, 45-64), median time from initial therapy to transplant was 36 months (range, 3-135 months). Disease phase prior to transplant was primary refractory in two patients, refractory relapse in 11 patients, sensitive relapse in eight patients and initial remission consolidation in one patient. The median number of prior therapies was five (range, 1-7), and median beta 2 microglobulin prior to transplant was 3.0 mg/l (range, 1.0-7.3). All patients received unmanipulated grafts from either HLA matched sibling donors (n = 13) or matched unrelated donors (n = 9). Eighteen patients received fludarabine 30 mg/m(2) for 4 days with melphalan 140 mg/m(2) as a single dose and four patients received fludarabine 25 mg/m(2) for 5 days with melphalan 90 mg/m(2) daily for 2 days. All 21 patients evaluable for engraftment achieved a neutrophil count of >0.5 x 10(9)/l after a median of 12 days (range, 9-24), 18 patients achieved platelet transfusion independence after a median of 14 days (range, 8-47). All engrafting patients had 100% donor cell engraftment. Seven patients achieved a complete remission. Six patients are currently alive with a median follow-up of 15 months (range, 10-47 months). The actuarial survival and progression-free survival is 30 +/- 11% and 19 +/- 9% at 2 years. Non-relapse mortality at 100 days was 19 +/- 10% and 40 +/- 10% at 1 year. Fludarabine/melphalan combinations are feasible and allow consistent engraftment of allogeneic progenitor cells from both related and unrelated donors in patients with multiple myeloma and should be explored in patients with less advanced disease.

Antineoplastic Agents↗
PubMed2002

Chronic graft-versus-host disease manifesting as polymyositis: an uncommon presentation.

Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation. Polymyositis can occur in association with chronic GVHD and mimics the idiopathic form of the disease. We report two cases of chronic GVHD-associated polymyositis and review the published literature. The two patients presented 13 and 19 months after allogeneic transplantation with characteristic features of muscular hypotrophy, proximal muscle weakness, pain, elevated creatine phosphokinase (CPK), aldolase and SGPT. Interestingly, both patients had HLA DR52 genes, which is frequently reported in association with idiopathic polymyositis. Electromyogram (EMG) and muscle biopsy confirmed the diagnosis. Treatment with cyclosporine or tacrolimus resulted in complete and sustained remission of polymyositis in both cases. A review of the literature shows cyclosporine and steroids are well-described treatment options for patients with myositis in post transplant, as well as idiopathic cases. The duration of immunosuppressive treatment has varied in different reports, and there is a risk of recurrence when immunosuppression is tapered.

Adult↗
PubMed2002

Comparison of competitive-nested PCR and real-time PCR in detecting BCR-ABL fusion transcripts in chronic myeloid leukemia patients.

Real-time RT-PCR has great advantages for estimating transcript levels in a variety of situations. These include relative rapid assay times (hours), reliability and ease of performing replicate analyses. In contrast, competitive PCR is a very labor-intensive procedure requiring a few days to generate useful data. We compared the same samples from CML patients by both methods. Importantly, we used the Bcr-Abl junction plasmid DNA, which is used as a competitor in the manual competitive PCR assay, to generate a standard curve for the real-time assay. This permitted reporting the real-time data as the number of BCR-ABL transcripts per microg of total RNA, which is the same format used for the competitive PCR assay. In this study, a total of 435 peripheral blood and marrow samples from 285 CML patients were analyzed by RT-PCR; these patients were undergoing therapy by STI-571, interferon, and bone marrow transplantation treatment. Most samples also had assay values for the Philadelphia chromosome (Ph), FISH and Western blotting for the Bcr-Abl oncoprotein. Our findings indicated that the real-time assay was less sensitive than the manual competitive RT-PCR assay (t = 5.118; P < 0.001). Of interest, the transcript levels in cell line mixtures with various ratios of K562/KG-1 (BCR-ABL positive/negative) cells were also significantly higher with the competitive RT-PCR assays than real-time RT-PCR, except for levels of BCR-ABL below 200 transcripts per microg of RNA. In both patient and cell line experiments, dividing the BCR-ABL transcripts by the total ABL transcripts virtually eliminated the difference between real-time BCR-ABL transcript values and quantitative competitive BCR-ABL transcript values, indicating that both BCR-ABL and ABL transcripts were underestimated by the real-time assay. In addition, the increased sensitivity of the nested, competitive RT-PCR was readily apparent in patients with minimal residual disease, which by the real-time were negative in the majority of patients but were positive by nested, competitive RT-PCR in 44.6% (n = 29) of samples analyzed (n = 65). These findings indicate that real-time RT-PCR, when normalized for the total ABL transcripts, can be used to monitor CML patients during therapy, but we suggest that nested, competitive RT-PCR be used to determine BCR-ABL/ABL transcript ratios at low transcript values or especially when real-time analyses are negative.

Fusion Proteins, bcr-abl↗
PubMed2001

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation.

The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P =.001), whereas the risk was increased with prior acute GVHD (HR, 1.67; P =.046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P <.001) and treatment failure (HR, 5.2; P <.001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.

Adolescent↗