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B Barlogie

Publications and source records attributed to B Barlogie.

At least 37 records · Page 2Linked to original sources
PubMed2002

Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications.

Thromboembolism is not uncommon in multiple myeloma (MM) patients on treatment, but its pathogenesis remains poorly understood. We report the results of a prospective randomized trial of 62 newly diagnosed MM patients tested at baseline for hypercoagulability and treated with intensive chemotherapy with or without thalidomide in a randomized fashion. During the induction phase, 12 patients (19%) developed evidence of deep venous thrombosis (DVT), which was significantly more common in the thalidomide arm (36%) than in the control group (3%) (P = 0.001). Fourteen patients (23%) were found to have a baseline-reduced response to activated protein C (APC) in the absence of factor V Leiden mutation. Using a Kaplan-Meier analysis, a significantly higher proportion of patients with APC resistance developed DVT (5/14 versus 7/38; P = 0.04) irrespective of thalidomide administration. The risk of DVT was highest (50%) in patients with APC resistance on thalidomide. None of the patients with normal APC response and not receiving thalidomide developed DVT. In conclusion, in this series, acquired APC resistance was present in almost one-quarter of newly diagnosed myeloma patients and significantly increased the risk of DVT.

Activated Protein C Resistance↗
PubMed2001

Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.

The occurrence of deep-vein thrombosis (DVT) in patients with newly diagnosed multiple myeloma, who were randomly assigned to receive identical induction chemotherapy with or without thalidomide, are reported in this study. The 2 study arms were comparable with respect to key myeloma prognostic factors and known risk factors for DVT. One hundred patients received induction chemotherapy including 4 cycles of continuous infusion of combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin, and each patient completed at least one induction cycle. DVT developed in 14 of 50 patients (28%) randomly assigned to receive thalidomide but in only 2 of 50 patients (4%) not given the agent (P =.002). All episodes of DVT occurred during the first 3 cycles of induction. Administration of thalidomide was resumed safely in 75% of patients receiving anticoagulation therapy. Thus, thalidomide given in combination with multiagent chemotherapy and dexamethasone is associated with a significantly increased risk of DVT, which appears to be safely treated with anticoagulation and does not necessarily warrant discontinuation of thalidomide.

Adult↗
PubMed2001

Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.

This report of a phase 2 trial of thalidomide (THAL) (200 mg/d; 200 mg increment every 2 weeks to 800 mg) for 169 patients with advanced myeloma (MM) (abnormal cytogenetics (CG), 67%; prior autotransplant, 76%) extends earlier results in 84 patients. A 25% myeloma protein reduction was obtained in 37% of patients (50% reduction in 30% of patients; near-complete or complete remission in 14%) and was more frequent with low plasma cell labeling index (PCLI) (below 0.5%) and normal CG. Two-year event-free and overall survival rates were 20% +/- 6% and 48% +/- 6%, respectively, and these were superior with normal CG, PCLI of less than 0.5%, and beta(2)-microglobulin of 3 mg/L. Response rates were higher and survival was longer especially in high-risk patients given more than 42 g THAL in 3 months (median cumulative dose) (landmark analysis); this supports a THAL dose-response effect in advanced MM.

Angiogenesis Inhibitors↗
PubMed2001

Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma.

Reciprocal chromosomal translocations, which are mediated by errors in immunoglobulin heavy chain (IgH) switch recombination or somatic hypermutation as plasma cells are generated in germinal centers, are present in most multiple myeloma (MM) tumors. These translocations dysregulate an oncogene that is repositioned in proximity to a strong IgH enhancer. There is a promiscuous array of nonrandom chromosomal partners (and oncogenes), with the 3 most frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-maf]) involved in nearly half of MM tumors. It is now shown that a novel t(6;14)(p21;q32) translocation is present in 1 of 30 MM cell lines and that this cell line uniquely overexpresses cyclin D3. The cloned breakpoint juxtaposes gamma 4 switch sequences with 6p21 sequences that are located about 65 kb centromeric to the cyclin D3 gene. By metaphase chromosome analysis, the t(6;14) (p21;q32) translocation was identified in 6 of 150 (4%) primary MM tumors. Overexpression of cyclin D3 messenger RNA (mRNA) was identified by microarray RNA expression analysis in 3 of 53 additional primary MM tumors, each of which was found to have a t(6;14) translocation breakpoint by interphase fluorescence in situ hybridization analysis. One tumor has a t(6;22)(p21;q11) translocation, so that cyclin D3 is bracketed by the IgL and IgH breakpoints. These results provide the first clear evidence for primary dysregulation of cyclin D3 during tumorigenesis. It is suggested that the initial oncogenic event for most MM tumors is a primary immunoglobulin translocation that dysregulates cyclin D1, cyclin D3, and other oncogenes to provide a proliferative stimulus to postgerminal center plasma cells.

Bone Marrow Cells↗
PubMed2001

Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003).

Current information on Waldenström macroglobulinemia (WM) is based on retrospective or single-institution studies of patients requiring therapy. Between 1992 and 1998, 231 patients with WM were enrolled in a prospective observational multicenter clinical trial. Of these, 182 patients with symptomatic or progressive disease were treated with 4 to 8 cycles of therapy with a purine nucleoside analogue, fludarabine (FAMP; 30 mg/m(2) of body-surface area daily for 5 days every 28 days). A serum beta2-microglobulin (beta2M) level below 3 mg/L and a hemoglobin level of at least 120 g/L (12 g/dL) at presentation predicted a lower likelihood of requiring therapy. The overall rate of response to FAMP therapy was 36% (95% confidence interval, 29%-44%), with 2% complete remissions. Patients who were 70 years old or older had a substantially lower likelihood of response (odds ratio, 0.34; P =.004) than younger patients. On multivariate analysis, a serum beta2M level of 3 mg/L or higher, hemoglobin level below 120 g/L, and serum IgM level below 40 g/L [4 g/dL] were significant adverse prognostic factors for survival. We developed a simple staging system for WM by using these variables and identified 4 distinct subsets of patients with estimated 5-year overall survival rates of 87%, 64%, 53%, and 22%, and 5-year progression-free survival rates of 83%, 55%, 33%, and 12%. Prognosis in WM is highly variable and serum beta2M was the dominant predictor of a need for therapy and of survival. FAMP has activity against WM. Our staging system may provide guidance for a risk-based approach to the treatment of WM.

Age Factors↗
PubMed2001

High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions.

Standard allogeneic stem cell transplant (allo-SCT) regimens have been associated with a high transplant-related mortality (TRM) in multiple myeloma (MM). Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. We report on 16 poor-risk MM patients receiving allo-SCT from an HLA-matched (n = 14) or mismatched (n = 2) sibling following conditioning with melphalan 100 mg/m(2) (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7) prior autotransplants. Donor lymphocyte infusions (DLIs) were given to 14 patients with no clinical evidence of graft versus host disease (GVHD) either to attain full donor chimerism (n = 4) or to eradicate residual disease (n = 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day +21. No TRM was observed during the first 100 days. Acute GVHD developed in 10 patients; 1 had fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and extensive in 4 patients. At a median follow-up of 1 year, 5 patients achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients progressing after transplantation, 3 achieved a remission following further chemotherapy and DLI. Remarkable graft versus myeloma responses were seen in chemotherapy-refractory patients. Two patients died of progressive disease, and 3 died of GVHD complications without active disease. GVHD remains a major problem with this procedure.

Adult↗
PubMed2001

Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells.

Multiple myeloma (MM) is a B-cell malignancy. The monoclonal immunoglobulin, secreted by myeloma plasma cells, carries unique antigenic determinants (idiotype [Id]) that can be regarded as a tumor-specific antigen. Id-based immunotherapy has been explored in myeloma patients for the purpose of enhancing or inducing Id-specific immune responses that might lead to tumor destruction. However, despite some evidence obtained from mouse plasmacytoma models, it is still unclear whether Id-specific immunity may play a role in the regulation of tumor cells in MM. In the current study, using dendritic cells (DCs) as antigen-presenting cells, autologous Id-specific cytotoxic T lymphocyte (CTL) lines containing both CD4+ and CD8+ T cells were generated from myeloma patients. The results show that Id-specific CTLs not only recognized and lysed autologous Id-pulsed DCs but also significantly killed the autologous primary myeloma cells. The cytotoxicity against the primary tumor cells was major histocompatibility complex (MHC) class I- and, to a lesser extent, class II-restricted, indicating that myeloma cells could process Id protein and present Id peptides in the context of their surface MHC molecules. Furthermore, the CTLs lysed the target cells mainly through the perforin-mediated pathway because Concanamycin A, but not Brefeldin A-the selective inhibitors for perforin- or Fas-mediated pathways-abrogated the cytolytic activity of the cells. These CTLs secreted predominantly interferon-gamma and tumor necrosis factor-alpha on antigen stimulation, indicating that they belong to the type-1 T-cell subsets. Taken together, these findings represent the first demonstration that Id-specific CTLs are able to lyse autologous tumor cells in MM and, thus, provide a rationale for Id-based immunotherapy in the disease.

Antigens, Neoplasm↗
PubMed2001

Distinct T-cell clonal expansion in the vicinity of tumor cells in plasmacytoma.

BACKGROUND: Although various clinical observations suggested that myeloma cell growth might be modulated by the immune system, evidence supporting the in situ immunogenicity of myeloma cells remains scarce. The authors reasoned that if there is any specific T-cell/tumor cell interaction in myeloma, it is most likely reflected in the T-cell population in the vicinity of the tumor cells. METHODS: The authors used a molecular method to compare the T-cell populations in the vicinity of tumor cells with those in the peripheral blood in patients with plasmacytomas and multiple myeloma. RESULTS: Six patients were studied. When compared with the peripheral blood from the corresponding patients, T cells in the vicinity of tumor cells in five of the six patients showed significant contraction of the T-cell receptor (TCR) Vbeta repertoire. In addition to this, the T cells isolated from the sites of the tumor cells from four of these five patients also demonstrated significant increase in the number of TCR Vbeta gene families with restricted number of CDR3 size peaks and loss of the normal CDR3 size gaussian distribution pattern. These findings were observed in patients who experienced recurrence after allogeneic stem cell transplantation and also in those who had autologous stem cell transplant. They also were found in previously untreated myeloma patients. In all six patients, distinct TCR Vbeta recurring transcripts indicative of a T-cell clonal expansion were found in the vicinity of the tumor cells and either absent or detected at only a low frequency in the peripheral blood. CONCLUSIONS: Our results provide evidence for an in situ local T-cell clonal expansion in the vicinity of tumor cells and support the presence of specific T-cell/tumor cell interaction in myeloma.

Adult↗
PubMed2001

Thalidomide in the management of multiple myeloma.

Thalidomide has recently been shown to have significant activity in refractory multiple myeloma (MM). A follow-up of the original phase II trial, expanded to 169 patients, shows 2-year survival of 60%; patients receiving > or =42 g over 3 months had a higher response rate and superior survival than those receiving lower doses. The addition of thalidomide to dexamethasone and chemotherapy for the management of post-transplant relapses results in higher response rates. The early results of the Total Therapy II trial for newly diagnosed MM patients show an unprecedented complete remission (CR) and near-CR rate of 69% after two melphalan-based transplants (whether or not receiving thalidomide). In addition, available clinical trial information involving at least 20 patients confirms that thalidomide is active in one third of patients in single-agent trials for refractory disease, with response rates increasing to 50% to 60% in combination with dexamethasone and to as high as 80% in combination with dexamethasone and chemotherapy. When applied as primary therapy in smoldering myeloma, one third of patients experienced 50% paraprotein reduction (PPR); in combination with dexamethasone pulsing, 70% to 80% of symptomatic patients responded. Thus, thalidomide is a major new tool in the treatment armamentarium of MM. The virtual lack of myelosuppression makes it an ideal agent for combination with cytotoxic chemotherapy. Newer, more potent, and less toxic derivatives of thalidomide are being evaluated.

Angiogenesis Inhibitors↗
PubMed2001

High-dose therapy and innovative approaches to treatment of multiple myeloma.

High-dose therapy in multiple myeloma (MM) appears to be superior in terms of event-free survival and overall survival compared with conventional therapy. Melphalan-based high-dose therapy increases complete remission rates from 5% to 50% and extends event-free survival beyond 3 years and overall survival beyond 6 years. Critical disease features associated with durable complete remission, event-free survival, and overall survival include the absence of chromosome 13 deletion, low beta(2)-microglobulin, and low C-reactive protein levels. Data on 1,000 patients enrolled in tandem high-dose trials show that chromosome 13 deletion is an important prognostic feature. The timely application of a second cycle of high-dose therapy extends event-free survival and overall survival markedly in MM patients with low beta(2)-microglobulin levels. Long-term results of the total therapy trial indicate that patients who do not have chromosome 13 deletions and present with low C-reactive protein and beta(2)-microglobulin levels have longer complete remissions than patients lacking these prognostic factors. Thalidomide shows clear evidence of antitumor activity possibly because of its antiangiogenic activity. Magnetic resonance imaging (MRI) indicates that bone marrow lesions become smaller or disappear while patients receive dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation chemotherapy and that patients who have a compete remission after diagnostic MRI have a superior event-free and overall survival than those who still have persistent MRI lesions. Prospective trials are underway to evaluate the effectiveness of consolidation therapy (total therapy II).

Antineoplastic Agents↗
PubMed2001

Thalidomide in the management of multiple myeloma.

A phase II trial of thalidomide in refractory multiple myeloma was initiated using a dose schedule that escalated from 200 mg/d to 800 mg/d. More than two thirds of patients had cytogenetic abnormalities and more than half had received at least two cycles of high-dose therapy. A paraprotein reduction of at least 25% was noted in 37% of patients and 14% had either a complete remission (CR) or a near CR. No treatment-related mortality was observed. With a median follow-up of almost 2 years, the 2-year event-free survival (EFS) and overall survival (OS) estimates were 15% and 60%, respectively. A reduction of paraprotein levels by greater than 50% was associated with a significant reduction in bone marrow plasmacytosis and beta(2)-microglobulin levels (beta2M), and greater recovery of hemoglobin and IgM levels compared to patients whose paraprotein was reduced by a lesser degree. Responses occurred more frequently among patients with a lower plasma cell labeling index (PCLI) and normal cytogenetics. Comparing response and survival by thalidomide dose for low- and high-risk groups revealed a thalidomide dose-response effect in the high-risk group of patients. The virtual absence of myelosuppressive toxicity, except in heavily pretreated patients with compromised bone marrow function, suggests that thalidomide is an ideal agent to be used in combination with cytotoxic agents and dexamethasone. Several trials are currently underway at the Arkansas Myeloma and Transplantation Research Center to determine the clinical benefit of adding thalidomide to post-transplant salvage therapy and in the upfront management of patients.

Angiogenesis Inhibitors↗
PubMed2001

Preceding chemotherapy, tumour load and age influence engraftment in multiple myeloma patients mobilized with granulocyte colony-stimulating factor alone.

Haematopoietic growth factors, especially granulocyte colony-stimulating factor (G-CSF), are frequently utilized alone for peripheral blood stem cell (PBSC) procurement to avoid the morbidity associated with high-dose chemotherapy (HDT). Moreover, the cytotoxic agents used may not be the most optimal therapy for the malignancy. It also makes scheduling of apheresis easier. Factors having an impact on PBSC procurement and engraftment after HDT were analysed in 117 multiple myeloma patients mobilized with G-CSF (10-16 microg/kg, median 12 microg/kg) alone using Cox regression analysis. A median of 6.2 x 10(6) CD34 cells/kg (range 0.6-34.1) were procured during leukapheresis and a median of 2.5 x 10(6) CD34 cells was infused after the first HDT (range 0.3-23.9). The only factor significantly affecting optimal PBSC procurement was duration of preceding conventional chemotherapy (P = 0.002). Granulocyte recovery was prompt in almost all patients, 75% of whom attained a granulocyte count of 0.5 x 10(9)/l by day 13 (median 11, range 7-19). However, platelet recovery to both 20 x 10(9)/l (median 12 d, range 8-50+) and 50 x 10(9)/l (median 20 d, range 7-205+) varied widely. On univariate analysis, factors influencing platelet recovery were the number of CD34 cells/kg infused, age, beta(2)-microglobulin levels, response to preceding therapy, bone marrow plasmacytosis and duration of prior therapy. Factors attaining significance on multivariate analysis included number of CD34 cells/kg infused (P = 0.007), beta(2)-microglobulin levels (P = 0.0001), most probably representing disease load, and age (P = 0.002). Patients with high tumour burden, i.e. beta(2)-microglobulin levels > 2.5 mg/l, probably benefit from chemotherapy for mobilization both in terms of cytoreduction and adequate stem cell mobilization resulting in accelerated engraftment.

Age Factors↗
PubMed2001

Cyclin D1 and E2F-1 immunoreactivity in bone marrow biopsy specimens of multiple myeloma: relationship to proliferative activity, cytogenetic abnormalities and DNA ploidy.

Cyclin D1, encoded by the CCND1 gene, is immunohistochemically detectable in up to one-third of cases of multiple myeloma (MM). To examine the mechanism of cyclin D1 overexpression, we compared cyclin D1 immunoreactivity with the results of conventional cytogenetics to determine if the t(11;14)(q13;q32) or other abnormalities of 11q11-14 explained cyclin D1 overexpression. Karyotypic abnormalities were found in 45 out of 67 (67%) MM cases; the t(11;14) was present in seven cases (10%). Additional 11q11-14 abnormalities were not identified. The t(11;14) correlated with cyclin D1 upregulation in low to intermediately proliferative MM, but was not present in highly proliferative tumours (assessed using bromodeoxyuridine labelling index). Cyclin D1 indirectly activates the transcription factor E2F-1. In the bone marrow biopsy specimens of MM cases, E2F-1 was concurrently expressed with cyclin D1 (P = 0.001), indicating that cyclin D1 is functional. However, as neither E2F-1 nor cyclin D1 expression correlated with proliferative activity, the speculation that t(11;14) upregulates the CCND1 gene to induce higher proliferation and possibly more aggressive disease is not supported. We conclude that in low to intermediately proliferative MM cases, cyclin D1 is probably upregulated by t(11;14), but an alternative mechanism is more probable in highly proliferative MM.

Adult↗
PubMed2001

Myeloma-reactive allospecific cytotoxic T lymphocytes lyse target cells via the granule exocytosis pathway.

Accumulating evidence indicates that a graft-vs.-myeloma effect (GVM) and its associated clinical remission of the disease can be induced by donor lymphocyte infusion in myeloma patients who have relapsed after allogeneic bone marrow transplantation. Although it is believed that GVM is induced by allospecific T cells, T-cell subsets and the mechanisms involved in the killing of myeloma cells by donor T cells have not been studied. In this study, we generated allospecific cytotoxic T lymphocyte (CTL) lines against three different myeloma cell lines, ARK, ARP-1 and U266, from unmatched healthy donors and examined their cytotoxicity against the target cells. Our results demonstrate that the allospecific CTLs efficiently lysed myeloma cells. The observed cytotoxicity was mediated mainly by CD8+ T cells and inhibited by MHC class I-blocking antibody. Furthermore, the CTLs lysed the target cells via the perforin-mediated pathway, as concanamycin A, but not brefeldin A (the selective inhibitors for perforin- or Fas-mediated pathways respectively) or tumour necrosis factor-alpha (TNF-alpha)-blocking antibody, abrogated the cytolytic activity of the cells. These CTLs expressed and produced predominantly TNF-alpha and interferon-gamma (IFN-gamma), indicating that they belong to the type 1 T-cell subsets. Taken together, these results indicate that CD8+ allospecific T cells may be responsible for mediating GVM and that the granule-mediated lysis of target cells is the major pathway in the CD8+ T-cell response against myeloma cells.

Adoptive Transfer↗
PubMed2001

Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma.

Multicolour spectral karyotyping (SKY) was performed on primary tumour specimens from 100 patients with multiple myeloma (MM) that showed complex clonal chromosome aberrations not fully characterized by G-banding. In this study, SKY was able to identify or revise translocations with breakpoints involving 14q32, 11q13 or 8q24 in 32 patients (32%). Five new recurring translocations were identified, two of which involved chromosome 22. A subtle reciprocal translocation t(14;22) (q32;q11 approximately 12) was identified using SKY in two patients and a second, much larger, translocation t(11;22)(q13;q13) was identified using G-banding in three patients. A third new translocation was identified in two patients using SKY and G-banding as der(7)t(7;7)(p15 approximately 22;q22 approximately 32). Twenty-three patients (23%) showed the loss of 8p by whole-arm translocations with different whole-arm donor chromosomes. Among this group, two new recurring whole-arm translocations involving the centromeric breakpoint 8q10 were identified as der(8;20)(q10;q10) and der(8;18) (q10;q10) in three patients each. In addition, a novel pattern of three-way translocations involving the clonal evolution of the t(8;22)(q24;q11) by the subsequent loss of 8p by whole-arm translocations was found in three patients. The chromosome instability identified here demonstrates that the loss of 8p can occur by multiple whole-arm translocations, indicating a new pathway for the loss of a specific chromosome region in MM.

Chromosome Deletion↗
PubMed2001

Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years.

The feasibility and efficacy of autologous stem cell transplantation (auto-SCT) in patients aged > or = 70 years was analysed. Newly diagnosed (n = 34) and refractory multiple myeloma (n = 36) patients were studied. The median age was 72 years (range: 70-82.6). CD34+ cells were mobilized with chemotherapy and granulocyte colony-stimulating factor (G-CSF) (n = 35) or G-CSF alone (n = 35), yielding medians of 11.8 x 10(6) versus 8 x 10(6) cells/kg respectively (P = 0.007). Because of excessive mortality (16%) in the first 25 patients who received melphalan 200 mg/m2 (MEL-200), the dose was subsequently decreased to 140 mg/m2 (MEL-140). Median times to absolute neutrophil count (ANC) > 0.5 x 10(9)/l and to platelets > 20 x 10(9)/l were 11 and 13 d respectively. Thirty-one patients (44%) received tandem auto-SCT. Complete remission (CR) was 20% after the first SCT and 27% after tandem SCT. Median CR duration was 1.5 years and was significantly longer for patients with < or = 12 months of prior chemotherapy (2.6 versus 1.0 years, P = 0.0008). The 3-year event-free survival (EFS) and overall survival (OS) (+ standard error, SE) were projected at 20% + 9% and 31% + 10% respectively. Tandem SCTs positively affected EFS (4.0 versus 0.7 years; P = 0.003) and OS (4.0 versus 1.4 years; P = 0.02) compared with single auto-SCT. In conclusion, MEL-140 is less toxic and appears equally as efficacious as MEL-200 in elderly patients. The benefits of tandem SCT in this patient population need further evaluation in a randomized trial.

Aged↗