Biomedical subjects
B Barlogie
Publications and source records attributed to B Barlogie.
Low-risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support.
To improve the safety of autotransplantation for myeloma, peripheral blood stem cell (PBSC) collection was attempted in 75 previously treated patients after the administration of high-dose cyclophosphamide (HD-CTX; 6 g/m2) with or without granulocyte-macrophage colony-stimulating factor (GM-CSF). Sixty patients subsequently received melphalan 200 mg/m2 (57 patients) or melphalan 140 mg/m2 and total body irradiation (850 cGy) (3 patients) supported by both autologous bone marrow and PBSC; 38 patients received GM-CSF posttransplantation. Among 72 patients undergoing PBSC apheresis, "good" mobilization (greater than 50 colony-forming units granulocyte-macrophage [CFU-GM] per 10(5) mononuclear cells) was achieved when prior chemotherapy did not exceed 1 year and when GM-CSF was used post-HD-CTX; similarly, rapid platelet recovery to 50,000/microL within 2 weeks was associated with "good" PBSC mobilization. These same variables also predicted for rapid engraftment after autotransplantation, so that hematologic recovery (granulocytes greater than 500/microL and platelets greater than 50,000/microL) proceeded within 2 weeks among the 37 patients with "good" PBSC collection. As a result of rapid neutrophil recovery (greater than 500/microL) within a median of 2 weeks, infectious complications both post-HD-CTX and posttransplant were readily manageable, resulting in only one treatment-related death post-HD-CTX. The cumulative response rate (greater than or equal to 75% cytoreduction) for all 75 patients was 68%, with 12-month event-free and overall survival projections of about 85%. Using both bone marrow and PBSC together with GM-CSF, autotransplants are safe and appear effective in myeloma, especially when prior therapy had been limited to less than 1 year. More than 80% of transplanted patients achieved complete hematologic recovery within a median of 1 month posttransplant (granulocytes greater than 1,500/microL; platelets greater than 100,000/microL; hemoglobin greater than 10 g%), thus providing sufficient hematopoietic reserve for further chemotherapy in the event of posttransplant relapse.
Primary dexamethasone treatment of multiple myeloma.
Intermittent courses of dexamethasone (DEX) were administered to 112 consecutive, previously untreated patients with multiple myeloma (MM). Using criteria based on a 75% or greater reduction of calculated tumor mass, the overall response rate was 43%. Among comparable patients, response rate were approximately 15% less than those observed previously with vincristine-doxorubicin by continuous infusion with intermittent DEX (VAD) and similar to those with melphalan-prednisone. The projected survival times with VAD or DEX were similar. Results indicated that DEX accounted for most of the plasma cell reduction achieved with VAD. Serious complications occurred in 27% of patients treated with VAD, but in only 4% of those who received DEX. In view of the similar outcome with fewer serious complications, DEX provided a simple, effective, and safe primary treatment for a large fraction of patients with MM. Patients who appear most likely to benefit include those with hypercalcemia or pancytopenia, or who require simultaneous radiotherapy for a pathologic fracture.
Interleukin-6 fused to a mutant form of Pseudomonas exotoxin kills malignant cells from patients with multiple myeloma.
IL-6-PE4E is a recombinant protein consisting of interleukin-6 (IL-6) fused to a mutant form of Pseudomonas exotoxin in which four basic amino acids are changed to glutamate (PE4E). The chimeric toxin has been previously shown to specifically kill malignant hepatic, prostatic, epidermoid, and myeloma cell lines in vitro. To explore the possible clinical utility of IL-6-PE4E, particularly as an agent for ex vivo purging of marrow for autologous bone marrow transplantation (ABMT), we tested malignant cells from patients with multiple myeloma for sensitivity to this chimeric toxin. Ficoll-purified bone marrow cells were incubated with and without IL-6-toxin for 2 to 3 days. Eight of the 15 myeloma patients had cells that were sensitive to IL-6-toxin as measured by a decrease in the level of protein synthesis. Cells from five patients were very sensitive to IL-6-PE4E, with 50% inhibition of protein synthesis (ID50) achieved at or below 6 ng/mL (7 x 10(-11) mol/L). Cells from three additional patients showed moderate sensitivity, with ID50s between 30 and 140 ng/mL. The remaining seven samples showed little or no sensitivity, with ID50s greater than or equal to 400 ng/mL. Normal bone marrow cells or normal BFU-E and CFU-GM were resistant to the IL-6-toxin even at 1,000 ng/mL. Neither IL-6, IL-2-PE4E, nor an enzymatically deficient mutant of IL-6-PE4E was cytotoxic toward the myeloma cells, indicating that the cytotoxic effect of IL-6-PE4E required the adenosine diphosphate-ribosylation function as well as the specific ligand. Our data suggest that IL-6-toxin could be effective in ex vivo marrow purging in selected multiple myeloma patients who are candidates for ABMT, and that this toxin should also be investigated further for in vivo therapy.
Pathophysiology of human multiple myeloma--recent advances and future directions.
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Multiple myeloma and chronic lymphocytic leukemia: parallels and contrasts.
Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are closely related B-cell cancers. Parallel and divergent features of these diseases are reviewed. In MM, expression of multiple hemopoietic lineage-associated antigens on the malignant cells and the substantial likelihood of progression to acute myelogenous leukemia suggest transformation of a pluripotent stem cell. In CLL, transformation more likely involves a committed B-cell progenitor. Another difference is that clonal evolution with associated cytogenetic progression is common in MM but not CLL. Other data, including studies of proto-oncogenes and tumor suppressor genes, suggest that MM results both from increased proliferation and accumulation of tumor cells, whereas tumor cell accumulation is the predominant feature of CLL. These differences may be reflected in the seemingly greater role of cytokine abnormalities in MM progression. For example, osteoclast-activating properties of some cytokines account for bone involvement in MM but not in CLL. MM and CLL share common features such as stage-dependent anemia and immune deficiency. Both diseases respond to alkylating agents but vary markedly in their sensitivity to fludarabine (CLL greater than MM) and glucocorticoids (MM greater than CLL). Differences between these diseases in progression-free interval and survival may reflect different definitions of premalignant and malignant phases rather than biologic differences. Detailed comparisons between MM and CLL may provide additional insights into these and related B-cell cancers.
Autotransplants in myeloma.
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Autologous bone marrow transplantation for multiple myeloma.
Intensive cytotoxic chemotherapy is capable of more marked tumor cytoreduction including true complete remissions in multiple myeloma. Use of autologous marrow and blood stem cells as well as growth factors has reduced the risk of infection and severe extramedullary toxicities.
High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma.
OBJECTIVE: To evaluate serum lactate dehydrogenase (LDH) as a prognostic factor in previously untreated patients with multiple myeloma. DESIGN: Study of 391 consecutive patients with uniformly treated multiple myeloma, followed until death in 63% of patients. SETTING: Tertiary, referral cancer center. PATIENTS: A total of 391 consecutive, previously untreated, symptomatic patients with various stages of multiple myeloma. INTERVENTION: Various chemotherapy regimens that included doxorubicin or glucocorticoids, or both, with a consistent response rate (53%). MEASUREMENTS: Outcomes included clinical response based on a 75% reduction of calculated tumor load and survival time from treatment. Univariate and multivariate analyses were used. MAIN RESULTS: Eleven percent of patients showed a high serum LDH level of more than 5.0 mukat/L (300 U/L). An elevated LDH level was seen more frequently with a rise in the tumor load; an increased level was present in 26% of patients with high tumor mass. A high LDH level was associated with plasma cell leukemia or lymphoma-like clinical features (43%) and with plasma cell hypodiploidy (17%). Only 20% of patients with elevated LDH levels responded to chemotherapy compared with a response rate of 57% for patients with low levels of LDH. Using multivariate analysis, LDH was a significant independent predictor of response (P = 0.001), with an odds ratio of 0.25 (95% Cl, 0.11 to 0.57). A high LDH level was associated with a short median survival (9 months) and showed the highest relative risk (2.63; Cl, 1.75 to 3.95; P = 0.001). CONCLUSIONS: Elevation of the LDH level suggests the presence of occult extraosseous disease and high tumor mass. The LDH level is a predictor of a poor prognosis in selected patients who should be considered for early intensive treatment.
Toward a cure for multiple myeloma?
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A weekly cisplatin-based induction regimen for extensive non-small cell lung cancer. A Southwest Oncology Group study.
The purpose of this Phase II pilot study was to determine whether a dose-intensive regimen of weekly cisplatin combined with other active non-cross-resistant agents would improve the response rate and survival time of patients with extensive non-small cell lung cancer. Patients received cisplatin (50 mg/m2/wk) on days 1, 8, 15, 22, 36, 43, 50, and 57 combined with mitomycin C (8 mg/m2) on days 1 and 36, vinblastine (3 mg/m2) on days 8 and 43, and 5-fluorouracil (5-FU) (1 g/m2) by continuous infusion over 24 hours on days 15 and 50. Responding patients received consolidation therapy with cisplatin and etoposide (VP-16). Of 82 registered patients, 80 were eligible and 77 were evaluable for response. The overall response rate was 23% with 1 patient achieving a complete response (CR) and 17 patients achieving a partial response (PR). The median survival time was 4.6 months. The toxicity profile was not different from that described for standard-dose regimens. Although this regimen does not offer any benefit over standard-dose cisplatin regimens for patients with extensive non-small lung cancer, the weekly schedule permits a dose-intensive regimen with acceptable toxicity for tumors that may benefit from this approach.
Single- and double-stranded RNA measurements by flow cytometry in solid neoplasms.
We investigated the ability of single- and double-stranded RNA measurements to discriminate between neoplastic and non-neoplastic solid tissues. Sixty-one solid nonhematopoietic neoplasms, 10 reactive non-neoplastic lesions, and 26 normal tissue samples were the test materials. Single-stranded ribonucleic acid (s-RNA) levels and double-stranded ribonucleic acid (ds-RNA) excess in these specimens were defined in relationship to normal human lymphocytes. The mean s-RNA index in normal, reactive, benign, and diploid and aneuploid malignant tissue samples was 0.90, 1.54, 1.9, 1.2, and 2.2, respectively. For ds-RNA, the mean excess level for normal, reactive, benign, and diploid and aneuploid malignant specimens was 8.5%, 18.5%, 51.0%, 36.0%, and 41.3%, respectively. No statistical differences in s-RNA level were found between non-neoplastic and neoplastic tissue samples. A significant difference in ds-RNA excess was found between non-neoplastic and benign, and diploid and aneuploid malignant neoplastic tissue (P less than 0.001). The specificity of s-RNA level and ds-RNA excess was 94.4% and 100%, and the sensitivity was 29.5% and 67.2%, respectively. Notably, ds-RNA determinations identified 70.0% of the diploid neoplastic samples, in contrast to 20% by s-RNA. Our preliminary data suggest that ds-RNA may be a useful parameter and may complement DNA ploidy in identification of solid neoplasms, especially if the yield of intact cells is improved.
Alpha-interferon combination therapy of resistant myeloma.
Among 68 patients with resistant multiple myeloma, alpha-interferon was combined with either the VAD regimen for those in relapse, or high-dose dexamethasone for those who had never responded. Neither the response rate nor the survival time improved in comparison with similar treatments without interferon. Results affirmed no benefit with added interferon in myeloma patients with advanced disease resistant to standard therapies. Certain prognostic features for low likelihood of response and for short survival identified patients who should be considered early for intensive therapies that require bone marrow or blood stem cell support.
alpha-Interferon for remission maintenance: preliminary report on the Southwest Oncology Group Study.
This preliminary report focuses on the therapeutic role of interferon in a large randomized trial evaluating combination chemotherapy induction and interferon maintenance, as compared with no maintenance therapy, in patients with newly diagnosed multiple myeloma. The trial also included an evaluation of the combination of interferon and dexamethasone therapy for patients who failed to respond to induction chemotherapy or who had achieved only a partial remission. Case accrual is completed for remission induction with 505 eligible patients registered on study, but is still open for additional maintenance registrations. As of January 1991, 161 patients have been randomized to interferon versus observation, but the therapeutic results of this aspect of the study remain coded. Toxicity of interferon maintenance was generally of a mild to moderate degree, and less severe than that of the interferon/dexamethasone combination, which was due to the addition of steroid side effects. Among 41 patients who failed to achieve remission with chemotherapy, 13 (32%) achieved at least a partial remission with interferon/dexamethasone, and only five others (12%) have had progressive disease. Of 12 partial responders on induction chemotherapy, five (42%) achieved remission (75% tumor regression) with interferon/dexamethasone. To date, more than 65% of patients receiving interferon/dexamethasone remain alive, suggesting that this regimen will be useful for patients who fail to achieve remission with induction chemotherapy.
Bone marrow transplantation in multiple myeloma.
Modifications of standard therapy with melphalan and prednisone have not improved the prognosis of patients with multiple myeloma. Encouraging results with high doses of intravenously administered melphalan have generated interest in marrow-ablative therapy with hemopoietic stem cell support. Experience in about 400 patients receiving alkylating agents, sometimes with added total body irradiation, demonstrates partial remissions in virtually all patients with advanced and refractory myeloma, but complete remissions (CR) in less than one-half, even when transplants were performed for responsive disease with low tumor burden. Despite patient and disease heterogeneity, different sources of hemopoietic stem cells (allogeneic or autologous, bone marrow or blood), ex vivo purging of autografts, and different preparative regimens, some general recommendations can be made: (1) Allogeneic BMT should be reserved for patients under age 50, where transplant-related mortality can be expected not to exceed 30%; 40% will achieve CR with a 3-year relapse-free survival expectation of 70%, and (2) With autologous transplantation, low mortality under 10% and marked therapeutic benefit (greater than 30% CR, 80% overall survival at greater than 3 years) seem to be achievable mainly if performed when tumor bulk is low and standard doses of therapy are still effective. Because of the encouraging results even in patients older than 60 years, hemopoietic stem cell grafting should be seriously considered as part of an overall treatment strategy, in order to avoid irreversible normal hemopoietic stem cell damage from nitrosoureas and radiation to marrow-containing bones.
Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors.
Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen, 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma, whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse, none of whom achieved complete remission and who, as a group, had median durations of relapse-free and overall survival of only 8 and 7 months, respectively. Among the 41 remaining patients, there was only one early death, and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable, the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months, and 8 patients died within 15 months. By contrast, a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden, absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.
High-dose melphalan and granulocyte-macrophage colony-stimulating factor for refractory multiple myeloma.
High-dose melphalan has induced remissions in about 40% of patients with refractory myeloma, but the mortality has been high, at about 20%, due to complications of prolonged granulocytopenia. In an attempt to stimulate earlier granulocyte recovery, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously to 23 patients with refractory myeloma who had been treated with melphalan at a high dose of 100 mg/m2. Thirty-nine percent of patients achieved marked tumor cytoreduction by at least 75%, 2 died within 2 months from infectious complications during severe neutropenia; and median durations of relapse-free and overall survival were 7 and 10+ months, respectively. The nine patients presenting with both advanced age over 50 years and a long history of prior therapy of over 1 year required significantly longer median times of 31 days for granulocytes and of 63 days for platelets to reach safe levels of at least 500/microL and 50,000/microL, respectively, than the 14 remaining patients who had none or only one of these adverse features (21 and 26 days, respectively). In a historic control of 43 patients treated previously with high-dose melphalan but without GM-CSF, hematologic recovery to the aforementioned levels of granulocytes and platelets proceeded over almost 5 weeks, regardless of age and prior treatment exposure. Thus GM-CSF seems to hasten marrow recovery, especially in patients with adequate normal marrow stem-cell reserve as defined by younger age or less prior therapy. While not shortening the duration of neutropenia, GM-CSF dose increments (from 0.25 to 0.5 to 0.75 mg/m2) increased the incidence of severe toxicity from 0% to almost 40%, especially among older patients. These results support the usefulness of low-dose GM-CSF (0.25 mg/m2) in stimulating marrow recovery in selected patients with adequate marrow reserve treated with high-dose melphalan for refractory multiple myeloma.
A rare BclI RFLP in the putative oncogene bcl-1 locus.
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