Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.
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PMID:Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. 170 43

Stem-cell transplantation in conjunction with myeloablative therapy has evolved as a standard treatment option for patients with several hematologic malignancies, including chemosensitive, relapsed non-Hodgkin's lymphoma and untreated multiple myeloma. The pharmacologic basis for this treatment includes a favorable tumor dose-response curve that abrogates intrinsic drug resistance associated with these diseases and facilitates cure or prolongation of survival even in the absence of a cure. The belief that chronic lymphocytic leukemia (CLL) is a palliative disease of the elderly has been perpetuated, limiting the application of more aggressive therapies. The introduction of fludarabine and its use in combination with other agents has increased the morphologic complete response rate observed in the initial treatment of CLL, providing the rationale to explore further disease-consolidative therapies. Concomitant with this, several phase II studies have demonstrated the feasibility of performing both allogeneic and autologous stem-cell transplantation in patients with CLL. In this regard, allogeneic transplantation has produced prolonged remissions in young patients with relapsed and refractory CLL, but at the cost of high treatment-related morbidity and mortality. Application of "minitransplantation" regimens may temper the frequency of these complications and warrants further study. Autologous stem-cell transplantation has also been explored with promising disease-free survival outcomes in less heavily pretreated patients. However, relapses continue to be the most frequent source of late mortality, as has been observed previously with multiple myeloma. With scientific justification established in similar diseases and demonstrated feasibility with low morbidity, we believe the time for a randomized comparison of standard chemotherapy versus autologous stem-cell transplantation in CLL has arrived. Despite promising results observed with allogeneic transplantation, further refinements that broaden the patient eligibility and lower treatment mortality will be required before similar investigations can occur with this modality.
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PMID:Stem-cell transplantation in chronic lymphocytic leukemia: the time for designing randomized studies has arrived. 1007 61

The proteasome, which plays a pivotal role in the control of many cell cycle-regulatory processes, has become the focus of new approaches to the treatment of cancer, including B-cell malignancies, and the first proteasome inhibitor, bortezomib (VELCADE; formerly PS-341), has entered clinical trials. The proteasome controls the stability of numerous proteins that regulate progression through the cell cycle and apoptosis, such as cyclins, cyclin-dependent kinases, tumor suppressors, and the nuclear factor-kB. By altering the stability or activity of these proteins, proteasome inhibitors sensitize malignant cells to apoptosis. Bortezomib is a dipeptidyl boronic acid proteasome inhibitor that effectively and specifically inhibits proteasome activity. In preclinical studies, bortezomib and other proteasome inhibitors have shown activity against a variety of B-cell malignancies, including multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, and Hodgkin's lymphoma. These agents can induce apoptosis and sensitize tumor cells to radiation or chemotherapy. Based on these findings, phase I clinical trials were conducted with bortezomib in various solid and hematologic malignancies. In these studies, bortezomib was generally well tolerated with manageable toxicities. Phase II trials have been initiated for relapsed and refractory multiple myeloma, refractory chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Preliminary data from the multiple myeloma phase II study indicate that a significant number of patients responded to therapy or exhibited stable disease and that the drug had manageable toxicities. These findings, along with extensive preclinical data, suggest that bortezomib and other proteasome inhibitors may have far-reaching potential in the treatment of various cancers, including B-cell malignancies.
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PMID:Proteasome inhibitors in the treatment of B-cell malignancies. 1214 56

Overexpression of Bcl-2 oncogene has been clinically associated with an aggressive clinical course, chemotherapy and radiotherapy resistance, and poor survival in patients with malignant B-cell disorders. Patients with relapsed or refractory chronic lymphocytic leukemia, multiple myeloma, or non-Hodgkin's lymphoma have limited therapeutic options. Preclinical and early clinical data have shown that Bcl-2 oncoprotein can be decreased by Bcl-2 antisense therapy. Also, downregulation of Bcl-2 protein can result in reversal of chemotherapy resistance and improved antitumor activity of biologic agents. Various clinical trials are evaluating the role of targeting Bcl-2 as a mechanism to enhance the antitumor potential of chemotherapy and immunotherapy. Early results from these clinical studies are encouraging and confirm the proof of principle for antisense therapy. As current data mature, these trials will hopefully validate preliminary results and establish Bcl-2 antisense as an important addition to the current armamentarium used in the treatment of patients with B-cell neoplasms.
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PMID:Bcl-2 antisense therapy in B-cell malignant proliferative disorders. 1523 3

Previous studies showed that chronic lymphocytic leukemia (CLL) cells exhibit certain mitochondrial abnormalities including mtDNA mutations, increased superoxide generation, and aberrant mitochondrial biogenesis, which are associated with impaired apoptosis and reduced sensitivity to fludarabine. Here we report that CLL cells and multiple myeloma cells are highly sensitive to brefeldin A, an inhibitor of endoplasmic reticulum (ER) to Golgi protein transport currently being developed as a novel anticancer agent in a prodrug formulation. Of importance, brefeldin A effectively induced apoptosis in fludarabine-refractory CLL cells. Disruption of protein trafficking by brefeldin A caused the sequestration of the prosurvival factors APRIL and VEGF in the ER, leading to abnormal ER swelling and a decrease in VEGF secretion. Such ER stress and blockage of secretory protein traffic eventually resulted in Golgi collapse, activation of caspases, and cell death. Notably, the cellular sensitivity to this compound appeared to be independent of p53 status. Taken together, these findings suggest that malignant B cells may be highly dependent on ER-Golgi protein transport and that targeting this process may be a promising therapeutic strategy for B-cell malignancies, especially for those that respond poorly to conventional treatments.
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PMID:Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL. 1614 3

Targeted therapy for malignant hematologic disorders has become a realistic goal with the identification of novel antibodies that are designed to act against highly expressed antigens on malignant clones. CD52 is abundantly expressed on malignant lymphocytes in chronic lymphocytic leukemia (CLL). Alemtuzumab is a humanized monoclonal antibody that targets CD52 and induces cell death by several mechanisms that are still under investigation. The initial positive results of many clinical studies that explored the activity of alemtuzumab in relapsed and/or refractory CLL have provoked many oncologists to incorporate this agent into the treatment paradigm of this disease. Prophylactic antibiotics for the duration of therapy or until patients are no longer immunocompromised are recommended. This review summarizes the clinical experience with alemtuzumab that eventually led to its approval. Recent novel prognostic factors and trends in CLL therapy are also reviewed.
Clin Lymphoma Myeloma 2005 Sep
PMID:The emerging role of alemtuzumab in chronic lymphocytic leukemia. 1623 49

The anti-CD52 monoclonal antibody alemtuzumab is highly active in the treatment of chronic lymphocytic leukemia (CLL) in patients with previously treated, relapsed, and/or refractory CLL as well as in patients with previously untreated disease. The general immunosuppressive impact and toxicities associated with alemtuzumab therapy are largely predictable and manageable. In particular, cytomegalovirus (CMV) reactivation is now a well-documented complication in patients receiving alemtuzumab. This article discusses several strategies for monitoring and treating CMV reactivation in patients with CLL receiving alemtuzumab-based therapy and provides practical recommendations for CMV management by building upon the guidelines published previously in 2004.
Clin Lymphoma Myeloma 2006 Sep
PMID:Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. 1702 23

Immunomodulating drugs belong to a new class of therapeutic agents that have immunomodulatory, antiangiogenic and antiproliferative effects. Although the basis of anti-tumour activity of immunomodulating agents are not clear, results of clinical trials have demonstrated impressive activity in certain hemalogical disorders such as multiple myeloma (MM) and myelodysplastic syndromes (MDS). The peculiar properties of immunomodulating agents prompted investigators to test their role in patients with chronic lymphocytic leukemia (CLL). The efficacy of single-agent thalidomide in refractory CLL is disappointing, although its combination with fludarabine seems promising. Lenalidomide, a thalidomide analogue, is showing anti-tumour activity with durable response in refractory CLL. These preliminary results represent the basis for investigating the potential of lenalidomide in association with established chemotherapy regimens or as maintenance therapy.
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PMID:Immunomodulatory drugs in chronic lymphocytic leukemia: a new treatment paradigm. 1748 28

The use of nucleoside analog-based chemo-immunotherapeutic regimens over the last decade has significantly improved outcomes in patients with chronic lymphocytic leukemia (CLL). Nonetheless, virtually all patients with CLL relapse from chemoimmmunotherapy and current available therapies are not curative. Identifying therapies that effectively eliminate CLL cells and lack immunesuppression represent an exciting new therapeutic approach. IMiDs are a class of immunomodulating drugs that increase T-cell and NK-cell directed killing of tumor cells. The first generation molecule is thalidomide followed by a second generation molecule lenalidomide that lacks neurotoxicity and is being explored more extensively in clinical trials. Lenalidomide has been shown to benefit patients with multiple myeloma, myelodysplastic syndromes, and lymphoma. Initial reports in patients with relapsed and refractory CLL have shown promising responses. In a subset of patients with CLL complete responses have been noted. Subsequent studies, however, have suggested that this class of drug can also have serious and potentially life-threatening side effects including myelosuppression, tumor flare reaction and in a small subset of patients tumor lysis syndrome. Tumor flare with both thalidomide and lenalidomide appear to be disease specific to CLL and may reflect clinical manifestation of CLL tumor cell activation. As a consequence of these disease specific effects, the optimal safe dose of lenalidomide in CLL remains to be determined but appears to be lower than that tolerated in other B-cell malignancies. To date, biomarkers for response remain poorly defined and the relationship of clinical benefit to tumor flare is uncertain. This review examines the existing literature on the use of IMiDs in patients with CLL and provides suggestions for future research in this area.
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PMID:Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia. 2005 57

In recent years, considerable advances have been made in first-line treatment strategies for chronic lymphocytic leukemia (CLL). Combination of conventional chemotherapy with immunotherapeutic agents is currently considered the most active strategy, with improved progression-free survival and overall survival. However, patients are not cured and invariably experience relapsing disease requiring treatment. In contrast to the advances made in first-line treatment strategies, much less progress has been made for patients with relapsed and especially refractory CLL. The activity of most chemotherapeutic drugs used in CLL rely on intact p53 function, and repeated cycles of therapy might eventually result in drug resistance because of acquired cytogenetic alterations, mainly affecting genes involved in the p53 response. As a consequence, most commonly used treatment regimens are ineffective in patients with refractory disease. A number of promising alternative treatment approaches are currently under investigation. In this review, the approach to patients with relapsed and refractory CLL and current promising experimental treatment options for these distinct clinical patient categories are discussed.
Clin Lymphoma Myeloma Leuk 2010 Jun
PMID:Standards for the treatment of relapsed chronic lymphocytic leukemia: a case-based study. 2052 6


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