Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody.
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Adult↗
Biomedical subjects
B Barlogie
Publications and source records attributed to B Barlogie.
Limited value of myeloablative therapy for late multiple myeloma.
The utility of myeloablative therapy supported by autologous bone marrow (BM) or blood progenitor cells was assessed in 49 patients with multiple myeloma who had received at least 1 year of prior chemotherapy. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients with disease in resistant relapse despite treatment with vincristine-doxorubicin by continuous infusion with pulse dexamethasone (VAD), a 61% response rate was associated with a median remission time of 5 months. After primary resistance for more than 1 year, 6 of 15 patients responded and the overall survival was similar to that of control patients. For patients with melphalan-resistant disease that responded to VAD, the remission time was similar to that of control patients. Current myeloablative treatments supported by autologous BM or blood stem cells were useful to very few patients with multiple myeloma after the first year of chemotherapy.
Adult↗
Effect of low-dose granulocyte-macrophage colony-stimulating factor (LD-GM-CSF) on platelet transfusion-dependent thrombocytopenia.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor known to promote the proliferation and differentiation of precursors of granulocytes and monocytes. GM-CSF at standard doses (125-500 micrograms/m2) alleviates neutropenia secondary to cytotoxic chemotherapy, myelodysplastic syndromes, and aplastic anemia, but has minimal effect on anemia or thrombocytopenia. GM-CSF at doses < 30 micrograms/m2 has been reported to improve platelet counts in some patients exhibiting cytopenia related to hematologic disorders such as aplastic anemia and myelodysplastic syndrome. Low-dose GM-CSF (10-20 micrograms/m2) was evaluated in 20 patients with transfusion-dependent thrombocytopenia persisting after myeloablative cytotoxic chemotherapy or with disease-related cytopenia. Seven patients (35%) responded as defined by a reduction in the platelet transfusion requirements by at least 75%. Low-dose GM-CSF did not significantly increase neutrophil counts or decrease red blood cell transfusion requirements. These results indicate that low-dose GM-CSF has a thrombopoietic effect in about one-third of patients with platelet transfusion-dependent thrombocytopenia which has not been observed at higher doses.
Blood Platelets↗
Phase II study of carboplatin (CBDCA) in refractory multiple myeloma. A Southwest Oncology Group study.
Nineteen patients with multiple myeloma resistant to standard alkylating agent therapy or to the VAD regimen received carboplatin at a planned daily dose of 100 mg/M2 on four successive days. Two patients erroneously received a four-fold higher drug dose resulting in bone marrow aplasia and death without antitumor effect in one patient with post-mortem examination. No anti-tumor effect was observed among 15 patients evaluable for response (two lacked follow-up examination of tumor markers). Major toxicities were hematologic and included grade > or = III, leukopenia in 9, thrombocytopenia in 6 and anemia in 3 of the 17 evaluable patients. Their median survival was 9 months. These results indicate that carboplatin is inactive in refractory multiple myeloma.
Adult↗
Salvage therapy for multiple myeloma: the University of Arkansas experience.
OBJECTIVE: To summarize a spectrum of salvage regimens for multiple myeloma (MM) developed during the past decade. DESIGN: We reviewed the experience at the University of Arkansas in the management of patients with MM who failed to achieve remission ("primary unresponsive") or had a relapse despite myelosuppressive doses of chemotherapy ("resistant relapse"). MATERIAL AND METHODS: Results with use of the various chemotherapeutic protocols are presented, and multivariate regression analysis was applied to determine the independent contributions of certain factors toward event-free and overall survival. RESULTS: The VAD regimen (vincristine sulfate, Adriamycin [doxorubicin hydrochloride], and dexamethasone) yielded responses in 29% of previously unresponsive and 46% of relapsed cases of MM, in comparison with 25% and 21%, respectively, with use of dexamethasone only. Responses occurred more frequently when tumor cell RNA content was high, tumor burden was low, and duration of drug resistance was less than 1 year. The duration of survival in patients who received high doses of melphalan was decreased in those with increased serum levels of lactate dehydrogenase. EDAP (etoposide, dexamethasone, ara-C, and cisplatin) produced 75% or more tumor cytoreduction in 8 of 20 patients. Overall in patients with an increasing number of adverse factors, response rates and survival decreased progressively with less intensive therapy but were unaffected when more intensive therapy was used. In the multivariate analysis, the most important features for extended survival were a low beta 2-microglobulin level before transplantation and application of two bone marrow transplants within 6 months. CONCLUSION: Variables relative to the patient's overall medical condition, prior treatment, characteristics of MM at diagnosis, and response history should be carefully assessed to determine a plan for salvage therapy that will maximize the opportunity for sustained remission and survival.
Antineoplastic Combined Chemotherapy Protocols↗
Hematopoietic stem cell autografts in support of myeloablative therapy for multiple myeloma.
This paper reports the experience of a single investigator team on the use of autografting in support of myeloablative therapy for multiple myeloma. This demonstrates continued progress toward decreased morbidity, and virtual elimination of mortality, as a result of rapid hematopoietic recovery, due to the use of peripheral blood stem cell grafts in newly diagnosed patients receiving several non-cross-resistant induction regimens followed by two autologous transplants, complete remission rates in excess of 50% can be achieved. Prognostic factors have also been identified for event-free and overall survival.
Anti-Bacterial Agents↗
Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study.
PURPOSE: Standard therapy for multiple myeloma consists of cytotoxic chemotherapy plus glucocorticoids. Interferon (IFN) alfa maintenance is reported to prolong chemotherapy-induced remissions and survival. This study evaluates induction chemotherapy, glucocorticoids, and interferon maintenance in myeloma. PATIENTS AND METHODS: Five hundred twenty-two previously untreated myeloma patients were randomized to three chemotherapy regimens with differing glucocorticoid intensities. Patients who achieved remission were randomized to receive IFN or observation until relapse. Patients who failed to respond to chemotherapy received IFN alfa plus dexamethasone (DEX). RESULTS: Five hundred nine patients were eligible for induction chemotherapy. Chemotherapy with higher dose-intensity glucocorticoids yielded higher response rates and improved survival (P = .02 for the three-group comparison; P < .05 for each higher glucocorticoid arm v vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine, carmustine [BCNU], doxorubicin, and prednisone [VMCP/VBAP]). One hundred ninety-three patients who achieved remission were randomized to receive IFN alfa 3 MU three times weekly or observation. IFN was not superior to observation for relapse-free (P = .95) or overall survival (P = .39) from start of maintenance. Eighty-eight induction failures received 5 MU of IFN three times weekly plus DEX. Patients who received IFN/DEX had a median survival duration of 48 months from start of IFN/DEX. CONCLUSION: Higher-dose glucocorticoids increases frequency of response to chemotherapy and prolong survival in myeloma. IFN maintenance with the dose schedule used in this trial did not prolong relapse-free or overall survival. We cannot exclude a small effect of IFN, as most individual trials do not have sufficient statistical power. Meta-analysis of randomized trials evaluating IFN maintenance in myeloma might be of value. While IFN appeared ineffective, addition of higher-dose glucocorticoids improved outcome in myeloma.
Adult↗
Hemopoietic stem cell transplants for multiple myeloma.
Recently, high-dose therapy has been evaluated in patients with multiple myeloma, mainly with autologous transplant support. As a result of rapid hemopoietic engraftment with peripheral blood stem cells collected after chemotherapy and/or hemopoietic growth factor priming, procedure-related mortality has dropped to below 5%. When applied within 12 months from initial therapy, autologous transplants effect complete remissions in up to 50% of patients, with median event-free and overall survival durations on the order of 2.5 and 4 to 5 years, respectively. Complete response rates with allogeneic transplantation range from 30% to 50%, and procedure-related mortality is approximately 40%. Although the median durations of event-free and overall survival are shorter with allogeneic transplants, approximately 35% to 40% of patients survive with minimal disease for at least 5 to 6 years. Direct comparisons of standard therapy and autologous transplants have just begun.
Antineoplastic Combined Chemotherapy Protocols↗
Deletion of the retinoblastoma gene in multiple myeloma.
Deletion of the retinoblastoma gene (Rb-1) was found in more than 50% (12/23) of patients with multiple myeloma (MM) by fluorescence in situ hybridization (FISH). Myeloma cells were highly purified from bone marrow aspirates by flow cytometry and analyzed using probes specific for the Rb-1 gene and the centromeric region of chromosomes 13 and 21. Routine cytogenetics revealed abnormal chromosome 13 in only 17% (4/23) of these patients. No correlation between Rb-1 deletion and tumor stage, immunoglobulin isotype, anemia, serum beta-2 microglobulin levels, patient age or the extent of prior therapy was found. However, the high incidence of Rb-1 deletion detected by FISH suggests a role of this tumor suppressor gene in the biology of MM. Although allelic loss of the Rb-1 gene is unlikely to be the only genetic change necessary for the development of MM, it may be a relatively early event in MM unrelated to chemotherapeutic intervention. Since the Rb-1 gene suppresses IL-6 production and secretion, Rb-1 deletion may result in deregulation of IL-6 expression and hence expansion of IL-6 dependent myeloma clones.
Adult↗
Acquired factor VIII inhibitor associated with chronic interferon-alpha therapy.
Therapeutic use of interferon-alpha (IFN-alpha) has been associated with the development of a variety of autoimmune disorders. We describe a patient who received chronic treatment with IFN-alpha following autologous bone marrow transplantation for multiple myeloma. The patient developed an antibody inhibitor directed against factor VIII coagulant protein (FVIIIC) leading to a fatal hemorrhagic diathesis. The association between IFN-alpha therapy and autoimmune complications deserves wider recognition and further study.
Autoantibodies↗
Hematopoietic stem cell transplantation.
The isolation, purification, and in vitro expansion of the hematopoietic stem cell have allowed pretransplant immunologic and genetic manipulation. As a result, rapid allogeneic or autologous hematologic reconstitution with minimal graft-versus-host disease is possible in patients receiving high-dose chemotherapy.
Bone Marrow Transplantation↗
Recombinant human erythropoietin and the anemia of multiple myeloma.
The anemia of multiple myeloma (MM) is multifactorial, including physical replacement of normal hemopoiesis by tumor cells, renal failure and cytokines which contribute to the blunted erythropoietin (EPO) response observed in anemias of chronic disease. Recombinant EPO has been evaluated in anemic patients with stable multiple myeloma (< or = 10g% hemoglobin). Responses (> or = 2g% hemoglobin increase) were observed in 78% of 41 patients in two separate studies. Responses were associated with an increase in bone marrow erythropoietic cell compartment and reticulocytosis. Evaluation of potential parameters affecting response identified prolonged cytotoxic therapy for > 12 months, especially with alkylating agents and pre-treatment EPO levels > 100 U/L, both of which seemed to decrease the likelihood of EPO response. EPO is a safe and effective treatment for the anemia associated with MM.
Anemia↗
VM-26 in gastric cancer. A Southwest Oncology Group study.
The Southwest Oncology Group conducted a trial of VM-26 (teniposide) in patients with advanced gastric cancer. VM-26 60 mg/m2 i.v. infusion over 30-45 minutes was given daily for 5 days every 21 days. Twenty-one eligible patients with measurable disease and a SWOG performance status of 0-2 were analyzed for response and toxicity. Partial responses were seen in 2 of the 21 eligible patients (9.5%). Median survival was 3.8 months. Severe of life-threatening toxicity was observed in 13/21 (62%) patients. This included two drug related deaths related to neutropenic sepsis and seven other patients with grade 4 granulocytopenia (< 500/mm3). Liver dysfunction and hypotension were seen less often and were not dose limiting. Although the modest activity seen was comparable to that of VP-16 (etoposide) as a single agent, the hematologic toxicity observed in this trial would likely preclude further trials of VM-26 (teniposide) in advanced gastric cancer.
Adult↗
Fludarabine therapy in Waldenström's macroglobulinemia.
PURPOSE: To assess the response rate, remission duration, and survival of patients with Waldenström's macroglobulinemia treated with the adenine nucleoside analogue fludarabine. PATIENTS AND METHODS: Twenty-eight patients with Waldenström's macroglobulinemia, of whom only 2 were previously untreated, received fludarabine at a dose of 20 to 30 mg/m2 intravenously daily for 5 days (20 patients) or 30 mg/m2 intravenously daily for 3 days (8 patients). Treatment was continued until maximum response was achieved. Responding patients were followed with no further treatment until relapse. RESULTS: Ten patients responded (36%), including the 2 previously untreated patients and 8 of 26 patients (31%) who were resistant to prior therapies. Unmaintained remissions lasted for a median of 38 months. There were no fatalities associated with this treatment. Previously untreated patients and those with a primary resistant disease of relatively short duration were more likely to benefit from this treatment. CONCLUSION: Fludarabine is an effective salvage agent for the treatment of patients with resistant Waldenström's macroglobulinemia. Further investigations of fludarabine in untreated patients and in combination with other active agents are warranted.
Adult↗
Expression of interleukin-6 in Castleman's disease.
Although mixed forms of Castleman's disease (CD) may occur, two classically recognized forms are the angiofollicular (hyaline vascular [V]) variant and the plasma cell (P) variant. The two forms of CD differ greatly in their clinical and histopathologic manifestations. Plasma cell CD is characterized by the presence of hyperplastic germinal centers (GCs) and sheets of plasma cells in the interfollicular areas. In this study we demonstrated an abundant expression of interleukin-6 (IL-6) in most GC B cells and in the numerous immunoblastoid B cells in the mantle zone and interfollicular areas in CD-P. Patients with CD-P also have an elevated serum IL-6 level. The increased IL-6 production is responsible for the marked plasma cell infiltration in lymph nodes and bone marrow as well as for the elevated gammaglobulin level in serum. In contrast, CD-V is distinguished by the presence of atrophic GCs, which often are populated by cytologically atypical follicular dendritic reticulum (FDR) cells, as well as by sheets of T-zone plasmacytoid histiocytes and increased numbers of capillaries in the interfollicular areas. In contrast to the findings in CD-P, we did not observe significant expression of IL-6 in GC cells or in immunoblastoid cells in CD-V; this may account for the paucity of plasma cells in this form of CD. The reason for the atypical changes in FDR cells as well as the increases in T-zone plasmacytoid histiocytes and capillaries seen in CD-V are not known inasmuch as no cytokines, such as IL-1, IL-4, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or granulocyte colony-stimulating factor, were detectable in tissues. It is possible that in CD-V the atypical change in FDR cells could lead to a disturbance of B-lymphocyte/FDR cell interaction and subsequently to poor development of GCs. The study clearly indicates that the histopathologic and clinical features of CD vary greatly depending on the capacity of activated B cells to produce IL-6. However, lack of IL-6 secretion by GC cells alone cannot explain the histopathologic alterations in CD-V.
Castleman Disease↗
Pathogenic significance of interleukin-6 in angioimmunoblastic lymphadenopathy-type T-cell lymphoma.
Patients with angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma may develop hypergammaglobulinemia. Among four cases of AILD-type T-cell lymphoma that we have studied, we detected a correlation between the number of plasma cells in tissue and the extent of interleukin-6 (IL-6) expression in lymphoma cells. We did not detect IL-6 in three patients who had no hypergammaglobulinemia and whose tissues showed only minimal plasma cell infiltration. In the fourth patient we observed an abundant IL-6 production by lymphoma cells, which accounted for a B-cell plasmacytic tissue response and for hypergammaglobulinemia. The pathogenic significance of IL-6 was substantiated by a concomitant decrease in the serum IL-6 level, measurable tumor mass, and immunoglobulin levels, as well as by a decline in the proportion of plasmacytoid cells in peripheral blood promptly on administration of chemotherapy. Plasmacytoid B cells could be maintained in culture in the presence of IL-6, but viability was lost on co-incubation with anti-IL-6. Interleukin-1 and tumor necrosis factor were not produced by T lymphoma cells and were incapable of sustaining plasmacytoid B-cell viability in vitro. Small amounts of IL-4 were noted in T lymphoma cells. Thus, in this case of AILD-type T-cell lymphoma, tumor cells with a T-cell phenotype produced IL-6 in large quantities, explaining the accompanying B-cell and plasmacytic histologic changes and humoral disease manifestations, including marked hypergammaglobulinemia. Although not all cases of AILD-type T-cell lymphoma have an accompanying plasma cell proliferation and hypergammaglobulinemia, and although the cytokine network in these patients may be more complex than has been recognized, this case with IL-6 expression serves to illustrate the utility of cytokine assays in the analysis of the histopathologic and clinical heterogeneities of peripheral T-cell lymphomas.
Aged↗
An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas.
PURPOSE AND METHODS: Doxorubicin alone or with dacarbazine (DTIC; AD) is considered the best available therapy for metastatic adult sarcomas. Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen. This study was designed to determine if ifosfamide added to doxorubicin and DTIC (ADI) significantly effects toxicity, response rate, and survival. Patients with measurable metastatic or unresectable sarcoma were randomized to receive AD or ADI. Patients with chondrosarcomas, fibrosarcomas, and other sarcomas of bone were eligible, although those with osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and mesothelioma were excluded, as were patients with prior chemotherapy for sarcoma or prior doxorubicin. RESULTS: Between 1987 and 1989, 340 eligible patients were randomized. Significantly more myelosuppression, a higher response rate (17% v 32%; P < .002) and longer time to progression (4 v 6 months; P < .02) were observed for patients who received ifosfamide. An overall survival advantage for the two-drug regimen (12 v 13 months; P = .04) was not significant by multivariate analysis. CONCLUSION: In all three randomized trials of doxorubicin with and without ifosfamide (Eastern Cooperative Oncology Group [ECOG], European Organization for Research and Treatment of Cancer [EORTC], and this study), the response rate was higher for the ifosfamide-containing arm, significantly so in this and the ECOG studies. An improved response rate may be particularly important for the preoperative management of high-grade, borderline resectable lesions or pulmonary metastases, particularly in younger patients. In older patients, or for low-to intermediate-grade lesions, doxorubicin and DTIC followed by ifosfamide on progression is preferred.
Adolescent↗
Hemopoietic stem cell transplant for multiple myeloma (MM).
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Hematopoietic Stem Cell Transplantation↗