Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 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

Seven patients with autoimmune hemolytic anemia (AIHA) associated with an underlying lymphoproliferative disorder were treated with intravenous immunoglobulin. Five patients with chronic lymphocytic leukemia, a patient with Hodgkin's lymphoma with severe AIHA associated with a "warm" IgG antibody, and a patient with non-Hodgkin's lymphoma with an IgM "cold" antibody were treated with intravenous immunoglobulin G (0.4 g/kg) daily for five doses followed by maintenance therapy every 21 to 28 days if evidence of recurrence was noted. Two additional patients with refractory chronic lymphocytic leukemia and hypogammaglobulinemia were given maintenance therapy with intravenous immunoglobulin G every 21 days for previously recurrent AIHA and infections. Hematocrit levels of patients with AIHA stabilized followed by a gradual improvement at 21 days after intravenous immunoglobulin G infusion without steroids. Treatment with steroids and intravenous immunoglobulin G resulted in faster and higher increments in hematocrit levels in these patients. Other patients who had partial responses to steroids showed further improvement in their hematocrit levels by the addition of intravenous immunoglobulin G. Another patient with a cold agglutinin disease was refractory to intravenous immunoglobulin G therapy. Five patients with chronic lymphocytic leukemia and acute AIHA and two patients with previous recurrences of AIHA required maintenance intravenous immunoglobulin G every 21 days. All seven patients except one did not have any episodes of AIHA from six months to as long as four years while receiving the three-week intravenous immunoglobulin G therapy. These observations indicate a role for intravenous immunoglobulin G in the management of IgG-mediated but not IgM-associated autoimmune hemolysis in immunocompromised patients with lymphoproliferative diseases.
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PMID:Rapid transient reversal of anemia and long-term effects of maintenance intravenous immunoglobulin for autoimmune hemolytic anemia in patients with lymphoproliferative disorders. 340 Jun 63

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

Denileukin diftitox (Ontak) is a novel recombinant fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domain of diphtheria toxin linked to human IL-2. Denileukin diftitox specifically binds to IL-2 receptors on the cell membrane, is internalized via receptor-mediated endocytosis and inhibits protein synthesis by ADP ribosylation of elongation factor 2, resulting in cell death. This article focuses on the clinical trial that led to the US FDA approval of the drug for cutaneous T-cell lymphoma in 1999, and other investigational studies for hematologic malignancies, recurrent and refractory chronic lymphocytic leukemia, non-Hodgkin B-cell lymphoma, graft-versus-host disease and autoimmune disease, demonstrating the activity and adverse effects of the drug.
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PMID:Optimizing denileukin diftitox (Ontak) therapy. 1868 57

Alkylating agents form the basis of most combination treatment regimens for low-grade lymphoproliferative disorders. Bendamustine is a unique alkylating agent that has distinctive preclinical activity in cell lines resistant to other alkylators. Furthermore, clinical activity has been demonstrated in patients with alkylating agent resistant disease. Recently, larger studies have been organized to study the clinical effects of bendamustine further. In indolent B-cell non-Hodgkin lymphoma that is resistant to rituximab, bendamustine induced a remission in 77% of patients. Myelosuppression was identified as the most common toxicity. In 2 studies of similar populations of patients, the combination of bendamustine and rituximab induced remission 90% of patients with a median progression-free survival of 23-24 months. The overall remission rate was 59% in a prospective, randomized study of untreated patients with chronic lymphocytic leukemia, which was significantly greater than the rate of 26% in the chlorambucil control arm (P < 0.001). Combined with rituximab, bendamustine induces a remission in 67% of patients with relapsed or refractory chronic lymphocytic leukemia. Bendamustine is an active agent for the treatment of low-grade lymphoproliferative disorders and more study is needed to determine which dose and schedule is optimal, and which patients will derive the greatest benefit from its use.
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PMID:Bendamustine: a new look at an old drug. 1911 40

Limitations of therapeutic options for chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) have necessitated the development of novel treatments/strategies. Rituximab (chimeric anti-CD20 monoclonal antibody [mAb]) considerably improved therapeutic outcomes for patients with B-cell malignancies, particularly when combined with chemotherapy; outcomes, however, are limited by rituximab resistance or reduced response upon re-treatment. Novel anti-CD20 mAbs are in development that may enhance mAb therapy. Ofatumumab (human anti-CD20 mAb) induces highly potent cell lysis, including in cells with low CD20 expression, and is the most clinically advanced new anti-CD20 mAb. Positive phase III interim data for ofatumumab in fludarabine-refractory CLL that is also refractory to alemtuzumab or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy has led to FDA approval of this agent in this population. Preclinical and early clinical assessment of other novel anti-CD20 mAbs include: ocrelizumab, veltuzumab, GA101, AME-133v, and PRO131921; data suggest potential for improved efficacy over rituximab that will require substantiation in large-scale clinical trials. New treatment strategies and novel anti-CD20 mAbs have the potential to enhance long-term outcomes for CLL and NHL.
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PMID:The future of CD20 monoclonal antibody therapy in B-cell malignancies. 2036 64

Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m(2) per d days 1-10, consisting of grade 3-4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m(2) per d days 1-10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m(2) per d decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL.
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PMID:Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. 2045 54

The potent alkylating agent bendamustine has demonstrated substantial efficacy in patients with non-Hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), follicular lymphoma, and mantle cell lymphoma. Due to incomplete cross-reactivity between bendamustine and other chemotherapeutic agents, bendamustine has been extensively tested in the relapsed/refractory setting. Bendamustine is highly effective in rituximab-refractory NHL and in patients whose disease is refractory to chemotherapy, including other alkylating agents. It has also demonstrated considerable efficacy in previously untreated NHLs, both alone and in combination with rituximab or other chemotherapeutic agents. Studies suggest complete responses and durability of remission achieved with bendamustine are superior to those achieved with standard regimens. However, longer follow-up is needed to fully establish long-term response duration. Additionally, bendamustine is associated with hematologic toxicity and risk of infection, which must be carefully monitored and managed. This is particularly important in elderly patients with advanced disease. Increased understanding of the mechanisms of action of bendamustine and the efficacy of bendamustine in combination with rituximab in newly diagnosed or relapsed/refractory CLL and indolent lymphomas led to investigation of other combinations. Ongoing studies are examining bendamustine with bortezomib, lenalidomide, temsirolimus, ofatumumab, alemtuzumab, and other novel agents. Bendamustine is also undergoing clinical investigation in patients with relapsed/refractory diffuse large B-cell lymphomas, a patient population with limited therapeutic options currently. This review will summarize current clinical data regarding the efficacy and safety of bendamustine in patients with lymphoma and highlight ongoing clinical trials expanding the role of this alkylating agent in the treatment of hematologic malignancies.
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PMID:Bendamustine's emerging role in the management of lymphoid malignancies. 2153 Jul 69

Bendamustine and bendamustine/rituximab combinations have shown high efficacy in relapsed/refractory chronic lymphocytic leukemia (CLL) and indolent B-cell malignancies (non-Hodgkin lymphoma, NHL). No data exist about bendamustine retreatment after relapse, concerning efficacy and toxicity in this patient population. Eighty-eight outpatients (57 patients with CLL, 31 patients with NHL) who had previously been treated with bendamustine were retreated with a bendamustine regimen. Treatment consisted of bendamustine (B) or bendamustine + mitoxantrone (BM) or bendamustine + rituximab (BR) or bendamustine + mitoxantrone + rituximab (BMR). Median age was 72 years (50-88). A reversible grade 3 or 4 leukocytopenia or thrombocytopenia was observed in 24% and 13%, respectively. The overall response rate (ORR) was 76% (7% complete remission [CR], 69% partial remission [PR]) with 77% (6% CR, 71% PR) in CLL and 71% (8% CR, 63% PR) in NHL. ORR according to regimen was as follows: B: 57% (14% CR, 43% PR), BM: 70% (4% CR, 66% PR), BR: 55% (10% CR, 45% PR), BMR: 84% (7% CR, 78% PR). Bendamustine retreatment is feasible and achieves high response rates and some long lasting remissions.
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PMID:Retreatment with bendamustine-containing regimens in patients with relapsed/refractory chronic lymphocytic leukemia and indolent B-cell lymphomas achieves high response rates and some long lasting remissions. 2378 78

Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin's lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL.
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PMID:Ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. 2491 46


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