Biomedical subjects

Bart Barlogie

Publications and source records attributed to Bart Barlogie.

105 records · Page 6Linked to original sources

PubMed2002

Early results of total therapy II in multiple myeloma: implications of cytogenetics and FISH.

Long-term follow-up on Total Therapy I revealed, with a median follow-up of about 10 years, median durations of event-free survival (EFS) and overall survival (OS) of 37 and 80 mos in the 88% of patients lacking cytogenetic abnormalities (CA) of chromosome 13 compared to only 28 and 34 mos in those with CA 13. Total Therapy II (TT II) was developed to test whether more intensive remission induction and post-tandem transplant consolidation chemotherapy prior to interferon maintenance could further improve clinical outcome. All patients were also randomized to +/- thalidomide at a starting dose of 400 mg. Results obtained in the first 231 patients enrolled in TT II are presented for the two study arms combined (data for effect of thalidomide still blinded). Three-year projection of EFS and OS are 71% and 77%. On an intent-to-treat basis, 66% achieved complete remission (CR) or near-CR. Major independent adverse features associated with shortened survival included CA and chromosome 13 deletion using interphase FISH. CA identified 29 among 102 patients with FISH 13 deletion who had a very grave prognosis (3 yr EFS, 32%; OS 49%) compared to all remaining patients who enjoyed 3 yr EFS of 79% and OS of 83%. Thus, both cytogenetics and FISH are recommended in the initial evaluation of patients with MM.

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PubMed2002

The evaluation of gemcitabine in resistant or relapsing multiple myeloma, phase II: a Southwest Oncology Group study.

Gemcitabine is a cytosine arabinoside (Ara-C) analog with activity in many human tumor systems. We evaluated the drug's activity in resistant or relapsing multiple myeloma. Gemcitabine 1000 mg/m2 was administered as a 30 minute infusion on days 1, 8, and 15 of a 28-day cycle. No dose escalations were permitted and dose reductions were scheduled for hematologic toxicity. Twenty-nine eligible patients were entered into Southwest Oncology Group (SWOG)-9803. One patient received no treatment and 5 patients had inadequate response assessments. The major toxicity was hematologic with grade 3/4 neutropenia in 9 and grade 3/4 thrombocytopenia in 15 patients. No responses were seen. Stable disease was confirmed in sixteen patients (57%). Median survival was eight months. Gemcitabine as utilized in this trial has shown little activity and is not to be strongly considered for future multiple myeloma trials.

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PubMed2002

Predicting long-term (> or = 5 years) event-free survival in multiple myeloma patients following planned tandem autotransplants.

Although outcome in multiple myeloma (MM) patients has improved significantly with the introduction of autotransplants (AT), the curability of this approach remained to be demonstrated. Therefore, we analysed outcome and prognostic factors using a logistic regression model in 515 consecutive newly diagnosed and previously treated patients intended to receive melphalan-based tandem transplants with follow up of > or = 5 years. One quarter of patients had event-free survivals (EFS) > or = 5 years with no further relapses seen after 7 years (46 patients on plateau). On multivariate analysis, factors associated with EFS > or = 5 years were absence of chromosome 11 and 13 abnormalities (odds ratio: 6.1), < or = 12 months of preceding standard-dose therapy (SDT) (OR: 2.6) and beta-2 microglobulin (B2M) level < or = 2.5 mg/l at time of first AT (OR: 1.7). Patients with only favourable variables (25%) had a 7-year EFS in excess of 35%, compared with 15% and 10%, respectively, with one (43%) or two unfavourable variables (27%), and 0% for 5% of patients with three unfavourable variables (P < 0.0001). Using a 1-year landmark analysis to allow for guaranteed time and thereby excluding early treatment failures, attaining a complete remission (CR) had no significant effect on long-term survival. Our data are consistent with cure in MM patients with a CR duration . or = 7 years and re-establishment of a monoclonal gammopathy of undetermined significance (MGUS) phase in those with persistent evidence of disease post transplantation, but without disease progression > or = 7 years.

Antineoplastic Agents, Alkylating↗

PubMed2002

Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity.

Myeloma tumour growth, except in the most advanced stages of the disease, is restricted to the bone marrow. We used the severe combined immunodeficient-human (SCID-hu) host system, in which primary human myeloma cells grow in, disseminate to and interact with a human microenvironment, to study the interactions between myeloma cells and cells in the bone marrow microenvironment. We used inhibitors of osteoclast activity to determine the role of osteoclasts and their products in supporting myeloma cell growth. Treatment of myelomatous SCID-hu hosts with an inhibitor of osteoclast activity (pamidronate or zoledronate) or with a specific inhibitor of the receptor activator of NF-kappaB ligand (RANKL) halted myeloma-induced bone resorption, when present, and resulted in inhibition of myeloma cell growth and survival. In contrast, myeloma cells from patients with extramedullary disease had a different growth pattern in the SCID-hu hosts and were not inhibited by these interventions, indicating that, while still dependent on a human microenvironment, these cells no longer required the bone marrow microenvironment for survival. This study demonstrates the dependence of myeloma cells on osteoclast activity and their products, and highlights the importance of the myeloma-osteoclast-myeloma loop for sustaining the disease process. Breaking this loop may help control myeloma.

Animals↗

PubMed2002

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.

Adult↗

PubMed2002

Optimizing dendritic cell-based immunotherapy in multiple myeloma.

Vaccination with idiotype protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. These studies used immature DCs, which are less potent at activating T cells and could differentiate to macrophages once the cytokines were withdrawn. After intravenous administration, DCs accumulate in the lungs and liver for up to 48 h, thus reducing their potential to migrate to lymphoid organs and interact with T cells. To improve the efficacy of DC vaccination in myeloma, we investigated the use of idiotype-pulsed mature DCs administered subcutaneously. Five patients (three IgG and two IgA myeloma) with stable partial remission following high-dose chemotherapy were enrolled. DC vaccines were administered three times at 2-week intervals at least 4 months post transplantation. Idiotype-specific T-cell responses, detected using enzyme-linked immunospot (ELISPOT) (four patients) and proliferation (two patients) assays, were elicited in four and anti-idiotypic B-cell responses in all five patients. The cytokine-secretion profile of activated T cells demonstrated a type-1 response. A 50% reduction in serum M-component was observed in one immunologically responding patient that persisted for 6 months and stable disease (for 6 months) resulted in the other three patients. The remaining patient without an immune response to the vaccination relapsed. No major side-effects were noted. Thus, subcutaneous administration of idiotype-pulsed mature DCs induced idiotype-specific T- and B-cell responses. Current efforts are geared towards optimizing the conditions of DC generation and administration, and the development of in vitro assays to monitor the cytotoxicity of the T cells.

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PubMed2002

Beta(2)-microglobulin as a negative growth regulator of myeloma cells.

High beta(2)-microglobulin (beta(2)m) levels in myeloma correlate with poor prognosis. We hypothesized that beta(2)m may affect myeloma cell growth and survival. In this study, we examined the in vitro effects of beta(2)m on myeloma cells. Primary myeloma cells freshly isolated from patients and myeloma cell lines were used, cultured in the presence of beta(2)m, and monitored for growth and survival. Beta(2)m suppressed the growth of primary tumour cells and myeloma cell lines (ARK-RS, ARP-1, RPMI-8226, U266, ARH-77 and IM-9). High concentrations of beta(2)m induced apoptosis and cell cycle arrest. Beta(2)m-induced apoptosis was dependent on activation of a caspase cascade, inhibited by interleukin 6, and did not involve the surface death receptors, as receptor-neutralizing antibodies had no inhibitory effect. Beta(2)m-induced growth arrest was associated with downregulation of cyclins A and D2. Surprisingly, anti-beta(2)m antibodies did not block the effect of beta(2)m but were synergistic with beta(2)m, resulting in 90% growth inhibition and 70% apoptosis of myeloma cells. Whereas beta(2)m treatment resulted in slight upregulation of surface beta(2)m and major histocompatibility complex class I alpha-chain expression, treatment of myeloma cells with anti-beta(2)m antibodies alone or with beta(2)m resulted in significant downregulation of surface beta(2)m and class I molecules, suggesting that class I molecules may be involved in signal transduction. Our data demonstrate that beta(2)m plays an important role in regulating the growth and survival of myeloma cells in vitro and warrants further investigation to delineate the mechanisms of beta(2)m and anti-beta(2)m antibody-induced growth regulation of myeloma cells.

Apoptosis↗

PubMed2002

Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma.

Complete or partial deletion of chromosome 13 or translocations involving 13q (delta13) by conventional cytogenetic analysis confers a poor prognosis in multiple myeloma (MM) patients, even with timely application of tandem autologous transplants. It was recently suggested that the prognostic significance of delta13 is related to its frequent association with hypodiploidy but by itself does not have a poor prognostic significance. We therefore analysed our experience in 1475 consecutive MM patients in whom we intended treatment with tandem transplants after a melphalan-based conditioning regimen. Patients with abnormal cytogenetic analysis were grouped into hypodiploid/hypotetraploid, pseudodiploid and hyperdiploid groups, according to their modal chromosome number. Their event-free and overall survival were compared with those of patients with a normalkaryotype. Both hypodiploidy and delta13 were found to independently confer poor prognosis in MM patients. Furthermore, these parameters in combination with easily obtained pretransplant levels of beta-2 microglobulin and albumin define three groups of MM patients with clearly distinct outcomes.

Biomarkers, Tumor↗

PubMed2002

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.

High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

ABO mismatch may affect engraftment in multiple myeloma patients receiving nonmyeloablative conditioning.

BACKGROUND: Blood group incompatibility does not appear to affect the overall outcome in patients undergoing myeloablative conditioning before allogeneic BMT. Data on ABO-mismatched transplantation in the nonmyeloablative setting are limited. STUDY DESIGN AND METHODS: A retrospective analysis of the effects of ABO mismatches in multiple myeloma patients who received a nonmyeloablative conditioning regimen was conducted. RESULTS: Three of 27 patients received a minor ABO-mismatched graft, all with evidence of hemolysis before converting to donor ABO group on Days 10, 15, and 6. Six patients received a major ABO-mismatched graft; of these, three developed GVHD of more than grade 2 and subsequently converted to the ABO blood group of the donor on Days 38, 33, and 43. Of the three patients without GVHD, one rejected the allograft and had autologous reconstitution. One remained a mixed chimera to Day 100 despite three donor lymphocyte infusions, and one developed pure RBC aplasia. None of the ABO-matched patients rejected the graft, whether they developed GVHD or not. RBC transfusions were significantly higher in the major and minor ABO-mismatched patients than in the ABO-matched patients, with medians of 12 units (range, 2-35), 13 units (range, 5-18), and 4 units (range, 2-15), respectively (p = 0.02). ABO-matched patients had a similar incidence of GVHD, with 5 of 9 ABO-mismatched patients (56%) having more than grade 2 versus 10 of 18 (56%). Four of 9 ABO-mismatched patients (44%) were mixed chimeras up to Day 100 versus 2 of 18 ABO-matched patients (11%), and the difference was significant (p = 0.01). CONCLUSION: Patients with ABO mismatch had problems with engraftment, including graft rejection, pure RBC aplasia, and mixed-lineage chimerism. RBC transfusions were significantly higher in the ABO-mismatched recipients. GVHD may play a role in engraftment, possibly by facilitating the disappearance of native ABO antibodies via graft-versus-plasma cell effect. A prospective study to evaluate the effects of ABO mismatch on engraftment in the nonmyeloablative setting is needed.

ABO Blood-Group System↗

PubMed2002

High-dose therapy and immunomodulatory drugs in multiple myeloma.

The principle of alkylating agent dose intensity, especially with melphalan-based tandem autotransplants, has been effective in increasing the rate of complete remission beyond 40% and effecting 10-year survivorship in about 40% of the three fourths of patients presenting without cytogenetic abnormalities (Total Therapy I). Further dose escalation and post-transplant consolidation therapy, as practiced with Total Therapy II, seems to further improve results in these patients, but not in those with chromosome 13 abnormalities or lactate dehydrogenase elevation. Phase III trials for post-transplant relapse indicate higher complete remission and near-complete remission rates among patients randomized to thalidomide added to dexamethasone versus dexamethasone alone. In a phase I/II study, thalidomide derivative CC-5013, with less sedative and neurotoxic effects, promoted responses in eight of 15 patients with post-transplant relapse, refractory to other salvage therapies, at dose levels of > or = 25 mg daily. Based on a profound graft-vs-myeloma effect with allografts, mini-allotransplants were evaluated in 31 high-risk patients with cytogenetic abnormalities and prior autotransplants; all nine with responsive disease and only one prior autotransplant remain disease-free and alive. Such mini-allotransplants are now offered as consolidation after one standard autotransplant to patients with cytogenetic abnormalities. The systematic application of gene expression profiling attempts to classify multiple myeloma (MM) patients according to molecular features and to dissect the genetic basis for drug sensitivity or resistance. Given the availability of an expanding treatment armamentarium (eg, thalidomide, CC-5013, the proteasome inhibitor PS-341, farnesyltransferase inhibitors, IL-6 receptor antibody, endothelial receptor inhibitor), gene expression profiling is anticipated to help in the selection of agents with the greatest probability of activity toward individualized treatment. Careful scrutiny of gene expression will also help in the identification of unrecognized targets for therapeutic intervention.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Thalidomide paradoxical effect on concomitant multiple myeloma and myelodysplasia.

We present five cases of concomitant relapsed multiple myeloma and therapy related myelodysplasia (t-MDS). After treatment with thalidomide marked anti-myeloma activity was observed, but it was associated with rapid progression of the MDS clone to acute myeloid leukemia (AML). This paradoxical effect of thalidomide is concerning because there is increasing use of thalidomide in relapsed, heavily treated multiple myeloma patients who already have a higher propensity to develop MDS. The leukemic transformation in our cases most probably reflects the natural progression of MDS, though it clearly demonstrates that thalidomide is ineffective in controlling blast proliferation in t-MDS. More concerning, however, is the possibility that thalidomide, while suppressing the myeloma clone, eliminates inhibitory signals and subsequently stimulates the proliferation of the leukemic clone. The use of thalidomide should be carefully assessed in relapsed multiple myeloma patients with clinical and cytogenetic evidence of t-MDS.

Acute Disease↗

PubMed2002

CGO: utilizing and integrating gene expression microarray data in clinical research and data management.

Clinical GeneOrganizer (CGO) is a novel windows-based archiving, organization and data mining software for the integration of gene expression profiling in clinical medicine. The program implements various user-friendly tools and extracts data for further statistical analysis. This software was written for Affymetrix GeneChip *.txt files, but can also be used for any other microarray-derived data. The MS-SQL server version acts as a data mart and links microarray data with clinical parameters of any other existing database and therefore represents a valuable tool for combining gene expression analysis and clinical disease characteristics.

Computational Biology↗

PubMed2002

Multiple myeloma.

This update provides new insights into the biology, diagnosis, prognosis, and treatment of multiple myeloma (MM) and its complications. In Section I, Drs. John Shaughnessy, Jr., and Bart Barlogie first correlate global gene microarray expression profiling of patient MM samples with normal plasma cells to provide the basis for a developmental stage-based classification of MM. The powerful clinical utility of these analyses is illustrated in delineating mechanism of drug action, identifying novel therapeutic targets, and providing a molecular analysis not only of the tumor cell, but also of the tumor microenvironment, in MM. In Section II, Dr. Jean-Luc Harousseau reviews the rationale and current results of high dose therapy and autologous stem cell transplantation in MM, including optimal patient selection, prognostic factors, conditioning regimens, sources of stem cells, use of tandem transplantation, and maintenance therapy. He then provides an update on the results of allotransplantation approaches in MM, focusing on proposed methods to reduce toxicity and exploit the graft-versus-MM alloimmune effect by transplantation earlier in the disease course, T cell depletion, and nonmyeloablative transplantation. In Section III, Dr. G. David Roodman provides recent insights into the mechanisms of osteoclast activation, interactions between bone and MM cells, adhesive interactions in MM bone disease, and osteoblast suppression. These recent advances not only provide insights into pathogenesis of MM bone disease, but also form the framework for novel therapeutics. In Section IV, Dr. Kenneth Anderson provides an up-to-date discussion of the role of the bone marrow microenvironment in promoting growth, survival, drug resistance, and migration of MM cells and the signaling cascades mediating these sequelae. These studies provide the framework for evaluation of novel therapeutics targeting the MM cell-host interaction in vivo in animal models and in derived clinical trials.

Animals↗

PubMed2002

A multicenter phase II trial of 4'-iodo-4'deoxydoxorubicin (IDOX) in primary amyloidosis (AL).

INTRODUCTION: 4'-Iodo-4'-deoxydoxorubicin (IDOX) has been reported to bind to and lead to the catabolism of amyloid deposits. A multicenter study attempted to develop a dosing schedule to confirm those results. METHODS: Patients with biopsy-proven amyloidosis were required to have a cardiac ejection fraction > 50%, ventricular septal thickness < 20 mm, serum creatinine < 2.5 mg per dL, bilirubin < or = 2.0 mg per dL, neutrophils > 1,500 per microL, and platelets > 100,000 per microL. IDOX was administered intravenously over 1 hour at a dose of 15 mg per m2 once a week for 4 consecutive weeks. This therapy was repeated every 3 months up to 4 times. RESULTS: Twenty-five previously treated and 15 untreated patients with primary amyloidosis (AL) received therapy. Fifteen patients had > 3 g of protein per day in the urine. Eleven patients had an ejection fraction < 60%. One, 2, 3, 4, and 5 organ systems were involved in 22, 10, 4, 3, and 1 patient, respectively. The median time between diagnosis and initiation of IDOX was 17.4 months. There were 6 responses (15%). Twelve of the patients have died CONCLUSION: IDOX administered in this protocol was insufficiently active at the current dose.

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