Relationship between lenalidomide dose modification, duration of therapy, and long-term outcomes in patients with myelodysplastic syndromes
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Dose reductions or interruptions may be required to manage treatment-associated adverse events among patients with myelodysplastic syndromes (MDS) treated with lenalidomide; such modifications are recommended to sustain therapy and maximize treatment duration. The aim of this retrospective case-control study was to determine the relationship between lenalidomide dose modification (DM), duration of lenalidomide therapy (DOT), and patient outcomes in patients with MDS. Those patients with database follow-up >20 months (n = 305) were more likely to have received erythropoiesis-stimulating agents (ESAs) (P = 0.004), had longer median DOT (P < 0.001), and higher rate of DM (P < 0.001) versus those with shorter follow-up (n = 306). Multivariate analysis indicated that lenalidomide DM (odds ratio [OR] 1.08) and prior ESA treatment (OR 2.40) were significantly associated with longer follow-up; transfusion dependence before lenalidomide initiation was associated with a significantly shorter follow-up (OR 0.60). These data suggest that effective management of lenalidomide treatment using dose reduction and/or delay is associated with longer DOT, which can improve patient outcomes.Cite
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Histopathology
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The drugs used in myelodysplastic syndrome(MDS) are quite limited,and the prognosis of some types of MDS is worse.Recently,lenalidomide has gotten people' s attentions.Lenalidomide has been approved for the treatment of International Prognostic Scoring System (IPSS)-classified low-or intermediate-1-risk MDS associated with chromosome 5q31 deletion,with or without additional cytogenetic abnormalities.However,the mechanism of action of lenalidomide is still unclear.There are some research findings indicated that lenalidomide also has effect on others types of MDS,suggesting that it can be used more widely.The latest studies about efficacies of lenalidomide on MDS are reviewed in this article.
Key words:
Lenalidomide; Myelodysplastic syndromes
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The aim of this article is to discuss the relevant pathobiologic effects of lenalidomide and the most recent clinical evidence to support its use in patients with myelodysplastic syndrome.Lenalidomide is an immunomodulatory agent with biological activity in several hematologic malignancies, including myelodysplastic syndrome. The precise mechanism yielding benefit in patients with myelodysplastic syndrome and 5q- syndrome is not clear, but various molecular and pathogenic targets have been identified. Enhancement of cellular immunity through T-cell and NK-cell activation and suppression of inflammatory cytokines and pro-angiogenic peptides upon lenalidomide treatment has been demonstrated in in-vitro models of myelodysplastic syndrome. Furthermore, lenalidomide induces a direct cytotoxic effect against 5q- clones in leukemia cell lines and enhances ligand-induced erythropoietin receptor signaling in erythroid progenitors. Clinical trials with lenalidomide in myelodysplastic syndrome have supported the in-vitro evidence of karyotype-dependent activity by demonstration of a high frequency of cytogenetic and pathologic responses in patients with myelodysplastic syndrome and deletion of chromosome 5q. Lenalidomide was approved for the treatment of transfusion-dependent patients with low to intermediate risk myelodysplastic syndrome and chromosome 5q deletion.Lenalidomide is an active immunomodulatory agent for the treatment of myelodysplastic syndrome with encouraging erythropoetic and cytogenetic remitting activity that is karyotype dependent.
Hematology
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Lenalidomide is a second generation immunomodulatory agent (IMiD), which currently represents the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndrome (MDS) patients with deletion (5q). Lenalidomide has unique activity with a high transfusion independence rate observed in this subset of patients. In this article we summarize the clinical experience using lenalidomide for treatment of del (5q) MDS. We highlight the mechanism of action and the recent advances in understanding the biology of del (5q) MDS. We also explore its potential use and the efforts to further improve its activity in non-del (5q) MDS. Keywords: Lenalidomide, myelodysplastic syndromes, deletion 5q, non-del(5q), immunomodulatory agent (IMiD), bone marrow failure, anemia, cytokines, apoptosis, myeloblast
Bone marrow failure
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Myelodysplastic syndromes (MDS) are a heterogeneous group of blood diseases mainly affecting older people. Deletion of the long arm of chromosome 5 (del[5q]) is reported in approximately 10–15 % of all MDS cases. Lenalidomide is an immunomodulatory, anti-cytokine and anti-angiogenic agent, which leads to red blood cells transfusion independence in patients of lower risk MDS with del(5q). This review briefly describes role of lenalidomide in treatment of lower-risk MDS with del(5q) as well as non-del-5q MDS. Recent evidence also suggest a potential role of lenalidomide in combination with other agents for treatment of higher-risk MDS
Blood cancer
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Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide.Forty-three patients with transfusion-dependent or symptomatic anemia received lenalidomide at doses of 25 or 10 mg per day or of 10 mg per day for 21 days of every 28-day cycle. All patients either had had no response to recombinant erythropoietin or had a high endogenous erythropoietin level with a low probability of benefit from such therapy. The response to treatment was assessed after 16 weeks.Neutropenia and thrombocytopenia, the most common adverse events, with respective frequencies of 65 percent and 74 percent, necessitated the interruption of treatment or a dose reduction in 25 patients (58 percent). Other adverse events were mild and infrequent. Twenty-four patients had a response (56 percent): 20 had sustained independence from transfusion, 1 had an increase in the hemoglobin level of more than 2 g per deciliter, and 3 had more than a 50 percent reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83 percent, as compared with 57 percent among those with a normal karyotype and 12 percent among those with other karyotypic abnormalities; P=0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50 percent reduction in abnormal cells in metaphase, including 10 (50 percent) with a complete cytogenetic remission. After a median follow-up of 81 weeks, the median duration of transfusion independence had not been reached and the median hemoglobin level was 13.2 g per deciliter (range, 11.5 to 15.8).Lenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.
Ineffective erythropoiesis
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Lenalidomide is approved for the treatment of Low and Intermediate-1 risk International Prognostic Scoring System categorized myelodysplastic syndromes (MDS) with deletion (del (5q)), and has an evolving role in other subtypes of MDS. Severe cytopenias may emerge with lenalidomide treatment, which appear to be related to elimination of the dysplastic clone. Although guidelines based on expert opinion have been published, the optimum management of lenalidomide-induced cytopenias in MDS in the “real world” setting is still evolving. We report two illustrative cases of lenalidomide-induced cytopenias in patients with del (5q) MDS, present an updated review of the literature and provide practical guidance for the management of cytopenias during lenalidomide treatment of MDS.
Cytopenia
Expert opinion
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