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Blood Jun 2007In the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM.... (Review)
Review
In the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM. Here, we review the classification, clinical features, and diagnostic criteria of the disease. WM is a B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and a monoclonal immunoglobulin M (IgM) protein. The symptoms of WM are attributable to the extent of tumor infiltration and to elevated IgM levels. The most common symptom is fatigue attributable to anemia. The prognostic factors predictive of survival include the patient's age, beta(2)-microglobulin level, monoclonal protein level, hemoglobin concentration, and platelet count. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. Novel agents such as bortezomib, perifosine, atacicept, oblimersen sodium, and tositumomab show promise as rational targeted therapy for WM.
Topics: Antineoplastic Agents; Cytogenetic Analysis; Diagnosis, Differential; Humans; Immunoglobulin M; Immunophenotyping; Neoplasm Invasiveness; Waldenstrom Macroglobulinemia
PubMed: 17303694
DOI: 10.1182/blood-2006-11-055012 -
British Journal of Haematology Sep 2007Over time, Waldenström macroglobulinaemia (WM) has evolved conceptually from a clinical syndrome to a distinct clinicopathological entity. Progress is being made in... (Review)
Review
Over time, Waldenström macroglobulinaemia (WM) has evolved conceptually from a clinical syndrome to a distinct clinicopathological entity. Progress is being made in standardization of the disease definition and treatment response criteria, although nosologic controversies persist. According to the Second International Workshop on WM, the disease is defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow, with an associated immunoglobulin (Ig) M paraprotein. Disease symptoms are often divided into those related to tumour infiltration and those related to the rheological effects of the monoclonal IgM. As with other low-grade lymphomas, asymptomatic patients are observed only, with treatment reserved for symptomatic patients. There is no standard treatment for WM and choices include rituximab, alkylating agents, purine nucleoside analogues, alone or in combination, as well as autologous peripheral blood stem cell transplant in eligible patients. Novel treatments, such as bortezomib, oblimersen sodium, perifosine and others are being evaluated.
Topics: Antineoplastic Combined Chemotherapy Protocols; Diagnosis, Differential; Humans; Plasmapheresis; Splenectomy; Waldenstrom Macroglobulinemia
PubMed: 17672883
DOI: 10.1111/j.1365-2141.2007.06724.x -
Annals of Oncology : Official Journal... Feb 2006To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with... (Clinical Trial)
Clinical Trial
PURPOSE
To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC).
PATIENTS AND METHODS
Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks.
RESULTS
Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m2 for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m2, respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months.
CONCLUSIONS
The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m2 intravenously on day 6 every 3 weeks.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Irinotecan; Leukocytes, Mononuclear; Lymphopenia; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Oligonucleotides, Antisense; Thionucleotides
PubMed: 16322117
DOI: 10.1093/annonc/mdj067 -
Oncology (Williston Park, N.Y.) Nov 2004Most malignant plasma cells overexpress Bcl-2, which contributes to resistance against apoptosis induced by dexamethasone and other anticancer agents. Oblimersen sodium... (Review)
Review
Most malignant plasma cells overexpress Bcl-2, which contributes to resistance against apoptosis induced by dexamethasone and other anticancer agents. Oblimersen sodium (Genasense, previously known as G3139), an antisense oligonucleotide that specifically binds to bcl-2 messenger RNA, decreases production of Bcl-2 protein in both human myeloma cell lines, as well as in ex vivo purified myeloma cells, and enhances the cytotoxicity of dexamethasone and doxorubicin. Combining oblimersen with other anticancer agents represents a therapy-enhancing strategy to reverse the multidrug resistance seen in multiple myeloma (MM). Phase II trials are evaluating the potential role of oblimersen in reversing resistance to standard therapies. Preliminary results from these trials in patients with refractory or relapsed MM indicate that the combination of oblimersen with dexamethasone/thalidomide (Thalomid) or vincristine/doxorubicin/dexamethasone is active and well tolerated and that oblimersen may help overcome chemotherapy resistance and restore sensitivity to MM cells. A randomized phase III clinical trial comparing dexamethasone plus oblimersen with dexamethasone alone in patients with relapsed or refractory myeloma has completed enrollment, with results expected to be available in 2004. Future studies will focus on the role of oblimersen in combination with novel biologic agents such as bortezomib (Velcade).
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Doxorubicin; Humans; Multiple Myeloma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides; Treatment Outcome
PubMed: 15651173
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Nov 2004Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for... (Review)
Review
Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance. Previous studies have shown that reduction of bcl-2 expression by antisense therapy sensitizes cells to chemotherapy-induced apoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium (Genasense, previously known as G3139) enhances the apoptotic response in CLL cells to fludarabine (Fludara), corticosteroids, alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial in patients with refractory/relapsed CLL showed that patients with CLL were more sensitive to oblimersen than patients with solid tumors. The maximum tolerated oblimersen dose was 3 mg/kg/d, and the most common dose-limiting reaction was hypotension, frequently in association with high spiking fever. In this study, oblimersen displayed limited single-agent activity, including tumor lysis syndrome, transient decreases in circulating CLL cells, and reduction of splenomegaly and size of lymph nodes. Major responses were observed in 9% of patients. Subsequently, a phase III trial evaluating fludarabine and cyclophosphamide with or without oblimersen (3 mg/kg/d for 7 days) was initiated in patients with relapsed or refractory CLL. This trial recently completed accrual of 241 patients.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Remission Induction; Survival Analysis; Thionucleotides
PubMed: 15651175
DOI: No ID Found -
Clinical Genitourinary Cancer Mar 2013Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including... (Review)
Review
INTRODUCTION
Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms.
MATERIALS AND METHODS
PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology.
RESULTS
To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors.
CONCLUSION
Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Clinical Trials as Topic; Gossypol; Humans; Molecular Targeted Therapy; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides; Urogenital Neoplasms
PubMed: 23083798
DOI: 10.1016/j.clgc.2012.09.002 -
Annals of Oncology : Official Journal... Oct 2010The management of chronic lymphocytic leukemia (CLL) is currently undergoing a profound change. First, several new drugs have been approved (fludarabine, bendamustine... (Review)
Review
The management of chronic lymphocytic leukemia (CLL) is currently undergoing a profound change. First, several new drugs have been approved (fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab). In addition, novel monoclonal antibodies targeting CD20, CD23, CD37 or CD40, as well as drugs designed to interfere with central pathways regulating the cell cycle, the apoptotic machinery, or the leukemic microenvironment (flavopiridol, oblimersen, ABT-263 or lenalidomide) are being tested in clinical trials. Furthermore, improved protocols using reduced-intensity allogeneic progenitor cell transplantation makes it possible to offer this procedure to more patients with CLL. Finally, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current knowledge in this rapidly moving field.
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drugs, Investigational; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Transplantation, Homologous
PubMed: 20943609
DOI: 10.1093/annonc/mdq373 -
Oncology (Williston Park, N.Y.) Oct 2004The results of treatment for metastatic melanoma remain disappointing. Single-agent chemotherapy produces response rates ranging from 8% to 15%, and combination... (Review)
Review
The results of treatment for metastatic melanoma remain disappointing. Single-agent chemotherapy produces response rates ranging from 8% to 15%, and combination chemotherapy, from 10% to 30%. However, these responses are usually not durable. Immunotherapy, particularly high-dose interleukin (IL)-2 (Proleukin), has also shown a low response rate of approximately 15%, although it is often long-lasting. In fact, a small but finite cure rate of about 5% has been reported with high-dose IL-2. Phase II studies of the combination of cisplatin-based chemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy, have shown overall response rates ranging from 40% to 60%, with durable complete remissions in approximately 8% to 10% of patients. Although the results of the phase II single-institution studies were encouraging, phase III multicenter studies have reported conflicting results, which overall have been predominantly negative. Various factors probably explain these discrepancies including different biochemotherapy regimens, patient selection, and, most importantly, "physician selection." Novel strategies are clearly needed, and the most encouraging ones for the near future include high-dose IL-2 in combination with adoptive transfer of selected tumor-reactive T cells after nonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy, and the combination of chemotherapeutic agents and biochemotherapy with oblimersen sodium (Genasense).
Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Humans; Immunotherapy; Interleukin-2; Melanoma; Multicenter Studies as Topic; Neoplasm Staging; Prognosis; Randomized Controlled Trials as Topic; Skin Neoplasms; Survival Analysis; Temozolomide; Thionucleotides; Treatment Outcome
PubMed: 15609471
DOI: No ID Found -
Annals of Oncology : Official Journal... Jul 2009This randomized, phase II study assessed the activity of oblimersen sodium, a Bcl-2 antisense oligonucleotide, administered before docetaxel (Taxotere) to patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This randomized, phase II study assessed the activity of oblimersen sodium, a Bcl-2 antisense oligonucleotide, administered before docetaxel (Taxotere) to patients with castration-resistant prostate cancer.
PATIENTS AND METHODS
Chemotherapy-naive patients with prostate-specific antigen (PSA) progression and testosterone < or = 0.5 ng/ml received docetaxel 75 mg/m2 on day 1 or oblimersen 7 mg/kg/day continuous i.v. infusion on days 1-7 with docetaxel 75 mg/m2 on day 5 every 3 weeks for < or = 12 cycles. Primary end points were confirmed PSA response (Bubley criteria) and major toxic events.
RESULTS
Confirmed PSA response was observed in 46% and 37% of 57 and 54 patients treated with docetaxel and docetaxel-oblimersen, respectively. Partial response (RECIST) was achieved in 18% and 24%, respectively. Oblimersen added to docetaxel was associated with an increase in the incidence of grade > or = 3 fatigue, mucositis, and thrombocytopenia. Major toxic events were reported in 22.8% and 40.7% of patients with docetaxel and docetaxel-oblimersen, respectively.
CONCLUSIONS
The primary end points of the study were not met: a rate of confirmed PSA response >30% and a major toxic event rate <45% were not observed with docetaxel-oblimersen.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Infusions, Intravenous; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Thionucleotides; Treatment Outcome
PubMed: 19297314
DOI: 10.1093/annonc/mdn784 -
Clinical & Translational Oncology :... Jun 2023Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive... (Review)
Review
Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.
Topics: Humans; Proto-Oncogene Proteins c-bcl-2; Antineoplastic Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Apoptosis; Hematologic Neoplasms; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 36639602
DOI: 10.1007/s12094-022-03070-9