Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lenalidomide has been approved by the US Food and Drug Administration for the treatment of patients with myelodysplastic syndromes (MDS) with an interstitial deletion of the long arm of chromosome 5 and, more recently, in combination with dexamethasone for multiple myeloma in patients who received at least one prior therapy. This discussion examines several clinically relevant, practical considerations regarding dosing, monitoring, follow-up evaluation, adverse events, and available support for lenalidomide recipients and their prescribing physicians in the MDS setting.
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PMID:Practical considerations in the use of lenalidomide therapy for myelodysplastic syndromes. 1724 64

Lenalidomide is a novel analog of thalidomide with both immunomodulatory and antiangiogenic properties that are more potent than those same properties in the parent compound. Work in several antiangiogenic model systems has provided early evidence of potential mechanisms of its clinical activity. Recent US Food and Drug Administration approval of lenalidomide for patients with deletion 5q myelodysplastic syndromes and advanced multiple myeloma has provided impetus for further evaluation of this agent in solid tumors.
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PMID:Lenalidomide: immunomodulatory, antiangiogenic, and clinical activity in solid tumors. 1728 77

Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, which has pleotropic activity, including antiangiogenic and antineoplastic properties. This agent is the product of advances in the understanding of the biology of neoplastic cells, their interaction with the microenvironment and of the underlying molecular pathways. Lenalidomide has shown significant activity in refractory/resistant multiple myeloma, and further studies have shown its activity in other hematologic malignancies with some very encouraging results, especially in subsets of patients with myelodysplastic syndromes. This article reviews the data on lenalidomide use in patients with multiple myeloma, as well as in myelodysplastic syndromes, chronic lymphocytic leukemia and myelofibrosis with myeloid metaplasia.
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PMID:The evolving role of lenalidomide in the treatment of hematologic malignancies. 1730 44

Lenalidomide is an immunomodulatory drug that was developed by modification of the first-generation immunomodulatory drug thalidomide in a drug discovery program. Lenalidomide more potently regulates cellular immune and cytokine responses, while lacking the side-effect profile of thalidomide. The promising activity seen in multiple myeloma and myelodysplastic syndrome has led to its approval by the U.S. Food and Drug Administration in these conditions. The clinical results that we have seen so far, which demonstrate significant efficacy with a tolerable toxicity profile, provide a strong basis for the use of lenalidomide in other malignancies. Combination therapy with lenalidomide could enhance this agent's antineoplastic role; this is likely the position it will occupy in the armamentarium against cancer.
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PMID:Lenalidomide: the emerging role of a novel targeted agent in malignancies. 1735 46

Over the past 50 years, thalidomide has been a target of active investigation in both malignant and inflammatory conditions. Although initially developed for its sedative properties, decades of investigation have identified a multitude of biological effects that led to its classification as an immunomodulatory drug (IMiD). In addition to suppression of tumor necrosis factor-alpha (TNF-alpha), thalidomide effects the generation and elaboration of a cascade of pro-inflammatory cytokines that activate cytotoxic T-cells even in the absence of co-stimulatory signals. Furthermore, vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF) secretion and cellular response are suppressed by thalidomide, thus antagonizing neoangiogenesis and altering the bone marrow stromal microenvironment in hematologic malignancies. The thalidomide analogs, lenalidomide (CC-5013; Revlimid) and CC-4047 (Actimid), have enhanced potency as inhibitors of TNF-alpha and other inflammatory cytokines, as well as greater capacity to promote T-cell activation and suppress angiogenesis. Both thalidomide and lenalidomide are effective in the treatment of multiple myeloma and myelodysplastic syndromes for which the Food and Drug Administration granted recent approval. Nonetheless, each of these IMiDs remains the subject of active investigation in solid tumors, hematologic malignancies, and other inflammatory conditions. This review will explore the pharmacokinetic and biologic effects of thalidomide and its progeny compounds.
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PMID:The thalidomide saga. 1736 76

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 median age of patients with acute myeloid leukemia (AML) is 65 to 70 years. The majority of older patients with AML probably do not receive specific treatment, and those who receive standard regimens have a median survival time of less than 1 year. This suggests that, in general, older patients should receive investigational therapy; however, factors other than age influence survival after administration of standard treatment and need to be accounted for when making treatment recommendations. In some cases where investigational therapy is unavailable, palliative care may be the best option. Like AML, myelodysplastic syndrome (MDS) is a disease of the elderly. It is divided into higher and lower risk groups. The natural history of high-risk MDS (eg, > 10% marrow blasts) bears more resemblance to that of AML than to that of an indolent disorder; accordingly, similar therapeutic considerations apply. The more benign natural history of lower risk MDS leads to consideration of reduction in transfusion needs and improvement in quality of life as primary goals of therapy. Lenalidomide, azacitidine, and decitabine, each recently approved by the US Food and Drug Administration, are useful in achieving these objectives.
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PMID:Acute myeloid leukemia and myelodysplastic syndromes in older patients. 1748 90

Lenalidomide is an immunomodulatory agent approved for use in patients with myelodysplastic syndrome, and in combination with dexamethasone for refractory or relapsed multiple myeloma. Pulmonary toxicity is believed to be uncommon. In this report, we describe a patient receiving lenalidomide in whom dyspnea, fever, hypoxia, and diffuse pulmonary infiltrates developed. BAL demonstrated a significant lymphocytic alveolitis typical for hypersensitivity pneumonitis. Extensive workup for other causes, including infections, was negative. Finally, the patient had improvement in symptoms and oxygenation after withdrawing lenalidomide and recurrence of symptoms when the drug was restarted. Thus, the patient's clinical course and workup strongly support a diagnosis of lenalidomide-induced hypersensitivity pneumonitis-like syndrome. Physicians should be cognizant of this potential complication in patients receiving thalidomide or thalidomide-like drugs who present with fever and pulmonary infiltrates and fail to improve despite treatment with broad-spectrum antibiotics.
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PMID:Hypersensitivity pneumonitis-like syndrome associated with the use of lenalidomide. 1749 8

Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenalidomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with del(5)(q31). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the VSIG4, PPIC, TPBG, activin A, and SPARC genes up-regulated by >2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is antiproliferative, antiadhesive, and antiangiogenic and is located at 5q31-q32, within the commonly deleted region in MDS 5q- syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with del(5)(q31). SPARC may play a role in the pathogenesis of the 5q- syndrome.
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PMID:Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. 1757 24

The heterogeneity of myelodysplastic syndromes (MDS) has driven the search for unifying biologic and clinical features that would stratify patients into distinct prognostic and therapeutic subgroups. Cytogenetics has been shown to impact the course of myelodysplasia. Despite the presence of non-random cytogenetic abnormalities in approximately 50% of MDS patients, it is significant that only a proportion of metaphases may contain the abnormality. Clonality studies however show that the karyotypically normal metaphases are still part of the MDS clone. This would suggest that the chromosomal abnormality may not be the initiating lesion in MDS, and that the gross karyotypic changes represent clonal evolution in a genetically unstable population. Yet, as will be described below, specific cytogenetic abnormalities are associated with clinically and biologically distinct forms of the disease, most notable in the response of del(5q) patients to lenalidomide. One possible explanation for the appearance of non-random mutational events could relate to the interaction of MDS cells with their microenvironment. Whatever the initiating lesion in the MDS stem cell, the end result is a clonal expansion where the marrow becomes populated by the monoclonal progeny of this cell. Interaction of these cells with a microenvironment which has been shown to be rich in pro-apoptotic cytokines such as tumor necrosis factor alpha (TNFa), leads to increased genetic instability. Hypoxia mediated decrease in DNA repair enzymes could further accelerate mutational events culminating in accumulation of multiple chromosomal abnormalities. Some of these chromosomal changes are associated with increased sensitivity to specific drugs. Lenalidomide has shown a high degree of efficacy in MDS patients with del(5q), although the target for the drug is unknown since a small but significant subset of MDS patients without del(5q) abnormality also respond to the drug. In contrast, the molecular target for imatinib mesylate is known; mutations in tyrosine kinase receptor family of genes found in patients with t(5;12) and del(4q12) make these individuals sensitive to the drug. Patients with isolated trisomy 8 have an immune component to the disease phenotype which can be targeted by cyclosporine and or anti-thymocyte globulin (ATG), especially in the presence of a PNH (paroxysmal nocturnal hemoglobinurea) clone. In the absence of these specific cytogenetic abnormalities described above, the two FDA approved hypomethylating agents 5 azacytidine and decitabine should be considered as therapeutic alternatives.
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PMID:Current treatment options: impact of cytogenetics on the course of myelodysplasia. 1763 37


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