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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review summarises the mechanism of action of immunomodulatory analogues of thalidomide and their use in myelodysplastic syndromes. Thalidomide was found to have a response rate of approximately 20% in these patients. Lenalidomide--which is more potent and less toxic than thalidomide--has been used in three clinical trials and produced the best responses (60 - > 90%) in low- and intermediate-1-risk transfusion-dependent patients with del(5q). The responses are purely erythroid in nature, and are associated with major cytogenetic responses in > 50% of the del(5q) patients. Non-del(5q) low- and intermediate-1-risk transfusion-dependent patients also had a approximately 25% incidence of transfusion independence following therapy with lenalidomide. Median time to response is approximately 4 weeks and 90% of patients respond within 12 weeks. The precise mechanism of action remains unknown but anticytokine, antiangiogenic and immunomodulatory properties are thought to play a role.
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PMID:Immunomodulatory drugs in myelodysplastic syndromes. 1678 43

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration.
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PMID:Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: phase I clinical trial of three dosing schedules in patients with solid malignancies. 1689 62

Immunomodulatory drugs, such as thalidomide, lenalidomide (Revlimid, CC-5013) and actimid (CC-4047), have a broad spectrum of activity and have shown remarkable responses in patients with multiple myeloma and related hematological diseases, such as myelodysplastic syndrome. They are currently being tested in other cancer types. This review will focus on the preclinical and clinical activity of thalidomide and its more potent immunomodulatory derivatives that are used to treat multiple myeloma. They represent a new class of antitumor agents that not only target the tumor cell directly, but also have significant activity within the bone marrow milieu. These agents have shown high responses in all phases of multiple myeloma, including the upfront setting, relapsed refractory stage and also as maintenance therapy for the disease. They have been used in combination with dexamethasone, chemotherapy and, more recently, with other novel agents, such as proteasome inhibitors. Thalidomide and lenalidomide in combination with dexamethasone have recently been approved by the US FDA for the treatment of multiple myeloma.
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PMID:Therapeutic use of immunomodulatory drugs in the treatment of multiple myeloma. 1702 Apr 58

The IMiDs represent a new proprietary class of thalidomide analogues that possess greater potency and less toxicity than the parent compound. As a group, these agents share the pharmacologic property of modulating cellular response to ligand activation, the precise biologic effect of which is cell lineage and stimulant-dependent. Lenalidomide (CC-5013; Revlimid), a second generation IMiD, has shown significant erythropoietic activity in patients with lower risk MDS that have failed or are not candidates for recombinant erythropoietin treatment. Unlike cytokine therapy, lenalidomide suppresses select MDS clones and enhances erythropoietin receptor signaling to restore erythropoiesis. Activity is greatest in patients with interstitial deletions involving chromosome 5q31.1. A multicenter phase II study reported a 76 % overall transfusion response rate in transfusion-dependent patients with deletion 5q, with 67 % achieving transfusion independence after a median interval of 4.6 weeks of treatment. Cytogenetic responses were observed in 73% of patients with complete cytogenetic remission in 45% patients. Both transfusion response and cytogenetic response frequency were independent of karyotype complexity, raising excitement that this new treatment strategy might favorably alter the natural history of disease in higher risk patients with deletion 5q. Lenalidomide was approved by the U.S. Food and Drug Administration on December 27, 2005, for the treatment of IPSS Low and intermediate-1 risk MDS patients with del(5q) abnormality. A phase III Intergroup trial (ECOG 2905) will test the capacity to potentiate erythropoietin response by comparing response to lenalidomide monotherapy to the combination of darbepoetin and lenalidomide in non-deletion 5q MDS patients.
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PMID:Immunomodulatory drugs (IMiDs): a new treatment option for myelodysplastic syndromes. 1707 50

Lenalidomide has particular activity in patients with transfusion-dependent del(5q) myelodysplastic syndromes (MDS), but mechanistic information is limited regarding the relationship between erythroid and cytogenetic responses. We reviewed medical records from three distinct subgroups of del(5q) MDS patients who had unexpected effects with lenalidomide treatment: 1. two patients with complex karyotypes who achieved both cytogenetic remissions and transfusion independence; 2. two patients with 5q- syndrome who took lenalidomide for less than 12 weeks but remained transfusion independent for 15+ months still displaying del(5q) metaphases after 6 and 12 months; and 3. one patient who was a non-responder on lenalidomide during treatment but became transfusion independent for 13+ months after discontinuation. All but the latter patient in this series had reduction of affected metaphases, suggesting that erythroid responses might be mediated by result from partial or complete suppression of the malignant clone, either directly or indirectly through modulation of the bone marrow microenvironment. These clinical observations illustrate the heterogeneity of del(5q)MDS pathogenesis and the diversity of lenalidomide responses within this patient subset.
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PMID:Lenalidomide in the context of complex karyotype or interrupted treatment: case reviews of del(5q)MDS patients with unexpected responses. 1711 Nov 42

Defined by isolated del 5q and no excess of marrow blasts, the "5q- syndrome" is a specific type of myelodysplastic syndrome (MDS) with particular characteristics, including severe anemia, frequent thrombocytosis, typical dysmegakaryopoiesis and favorable outcome. Its pathogenesis remains uncertain, in particular the role of inactivation of gene(s) situated in 5q. It should be differentiated from other MDS with del 5q having an excess of marrow blasts and/or additional cytogenetic abnormalities, which carry a poor prognosis. Until the advent of lenalidomide, repeated RBC transfusions were generally the only treatment of the 5q- syndrome, which was resistant to other therapeutic approaches. Lenalidomide can lead to RBC transfusion independence in at least two thirds of cases of the 5q- syndrome, two thirds of those responses persisting after 2 years of treatment. Importantly, not only reversal of anemia but also frequent complete pathological and cytogenetic responses are obtained. Grade 3 or 4 neutropenia and thrombocytopenia, especially during the first 6 to 8 weeks of treatment, are the major side effect of lenalidomide, justifying close monitoring of blood counts and regular patient visits. Preliminary results suggest that lenalidomide is also very active in MDS with del 5q other than the 5q-syndrome. Although its mechanism of action remains uncertain, lenalidomide appears to target specifically the del 5q clone. By doing this, lenalidomide may have an effect on disease course and survival, which is currently being assessed in clinical trials.
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PMID:Treatment of the 5q- syndrome. 1712 60

In clinical practice, whether FISH for EGR1 in interphase nuclei has similar efficacy to detect deletion 5q anomalies as conventional cytogenetic studies is unknown. We compared conventional cytogenetics and FISH for 145 patients with deletion 5q and detected this anomaly by both methods in 144. Nine patients with myelodysplasia were studied before and after treatment with Lenalidomide and results were concordant for 28 of 29 specimens. FISH did not detect anomalies other than deletion 5q in 31 patients. This study suggests FISH is useful to detect deletion 5q, but is not a substitute for conventional cytogenetics.
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PMID:Efficacy of conventional cytogenetics and FISH for EGR1 to detect deletion 5q in hematological disorders and to assess response to treatment with Lenalidomide. 1712 35

Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected.
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PMID:Lenalidomide: targeted anemia therapy for myelodysplastic syndromes. 1724 61

Lenalidomide has emerged as an effective therapeutic alternative for the management of anemia in lower-risk myelodysplastic syndromes (MDS). Compelling results from phase I and phase II clinical studies prompted the US Food and Drug Administration to approve lenalidomide for the treatment of transfusion-dependent MDS patients with interstitial deletion of chromosome 5q [del(5q)]. Subsequently, the National Comprehensive Cancer Network (NCCN) has incorporated lenalidomide into their current treatment algorithm for the treatment of lower-risk del(5q) patients. This discussion examines the current NCCN guidelines for the treatment of these patients, including the management of anemia in lower-risk MDS, and discusses the potential future therapeutic applications of lenalidomide in this disease.
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PMID:Evolving applications of lenalidomide in the management of anemia in myelodysplastic syndromes. 1724 62

Lenalidomide has been approved for the treatment of transfusion-dependent low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We evaluated the cost effectiveness of lenalidomide versus best supportive care (BSC) in these patients. We developed a decision analytic model to compare costs and outcomes of lenalidomide with BSC without recombinant erythropoietin (EPO) versus BSC with EPO over 1 year. Outcome measures were transfusion independence and quality-adjusted life years (QALYs) gained. The model incorporated costs of medications, transfusions, chelation, laboratory tests, office visits, and other resources associated with each therapy. Lenalidomide therapy was associated with an estimated incremental 0.53 transfusion-free and 0.25 QALY gain compared to BSC at 1 year. The costs of lenalidomide therapy were substantially offset by reduced blood transfusion and EPO costs. One-year total treatment costs were estimated at $63,385 for lenalidomide and $54,940 for BSC. The incremental cost-effectiveness ratio for lenalidomide vs BSC was estimated at $16,066 per transfusion-free year and $35,050 per QALY gained, values within the acceptable cost-effectiveness ranges for a new therapy. Results suggest that oral lenalidomide is cost effective in the United States in the treatment of transfusion-dependent, low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality. Confirmation of these findings awaits results of an ongoing randomized phase III trial (MDS-004 study).
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PMID:Cost effectiveness of lenalidomide in the treatment of transfusion-dependent myelodysplastic syndromes in the United States. 1724 63


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