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Alan List

Publications and source records attributed to Alan List.

10 recordsLinked to original sources
PubMed2006

Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion.

BACKGROUND: Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31- clone in patients with this disorder. METHODS: One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis. RESULTS: Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached a median of 13.4 g per deciliter (range, 9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range, 1.1 to 11.4), as compared with the baseline nadir value before transfusion. Among 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated. Moderate-to-severe neutropenia (in 55% of patients) and thrombocytopenia (in 44%) were the most common reasons for interrupting treatment or adjusting the dose of lenalidomide. CONCLUSIONS: Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion. (ClinicalTrials.gov number, NCT00065156 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Immunomodulation in myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) - bone-marrow stem-cell malignancies that share pathogenetic overlap with acute myeloid leukemia - are characterized by peripheral-blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest. Premature apoptosis of bone-marrow cellular elements contributes to ineffective hematopoiesis, which is exacerbated by stromal production of inflammatory cytokines. Abrogation of the effects of these cytokines represents an area of active clinical research, particularly in the treatment of low-risk MDS. Agents such as thalidomide, lenalidomide, and infliximab have shown promising efficacy and tolerability in clinical trials, and may represent a springboard for future treatment combinations.

Humans↗
PubMed2005

Efficacy of lenalidomide in myelodysplastic syndromes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Adult↗
PubMed2005

Alternative treatments for myelodysplastic syndromes.

Selecting the most appropriate treatment for patients with myelodysplastic syndromes (MDS) requires careful consideration of several factors. Most patients with MDS are in the 7th or later decade of life and often have comorbid health problems influencing treatment tolerance. Poor-prognosis MDS, as indicated by unfavorable cytogenetics or an increased percentage of myeloblasts, warrants more aggressive interventions than more indolent forms, which might remain stable for many years without treatment. The only curative treatment for MDS is allogeneic stem cell transplantation; however, only a small percentage of patients are candidates for this aggressive treatment. Traditional management for most patients with MDS is supportive care with red blood cell and platelet transfusions or hematopoietic growth factor support and antibiotics for infections. More detailed scrutiny of the processes involved in the MDS phenotype has stimulated investigation into identifying alternate therapeutic options that are effective and better tolerated. Herein, we summarize an array of novel treatments in development for the management of MDS.

Alkyl and Aryl Transferases↗
PubMed2005

Immunomodulatory drugs.

After nearly decades of extinction as a sedative and antiemetic, thalidomide reemerged as the parent compound of a novel and promising class of therapeutics termed the immunomodulatory drugs (IMiDs). The analogues of thalidomide, CC-5013 (lenalidomide, Revlimid) and CC-4047 (Actimid) are more potent regulators of cellular immune and cytokine response while lacking some of the dose limiting side effects of the parent compound, such as neurologic toxicity. Preclinical data will be reviewed that outlines these drugs' effects on tumor necrosis alpha, interleukin 12, angiogenesis, and T-cell function. The evolution of the use of thalidomide as a therapeutic for diseases such as multiple myeloma and myelodysplastic syndrome and the promising initial results of the new IMiDs will be reviewed.

Humans↗
PubMed2005

Lenalidomide: an immunomodulatory drug.

Lenalidomide (CC-5013; Revlimid) represents one compound in a category of new medications known as immunomodulatory drugs. These compounds are thalidomide derivatives. Through relatively minor structural modifications, the potency of the medication is improved compared with the parent compound, and the side-effect profile has changed considerably. The neurologic toxicity and pro-thrombotic effects of thalidomide are reduced in the structural analog, although concerns regarding pro-thrombotic effects are still present when lenalidomide is combined with dexamethasone. Data supporting lenalidomide's use in myelodysplastic syndrome and multiple myeloma has been published over the past several years and presented at the May 2005 meeting of the American Society of Clinical Oncology. Further trials are ongoing for many other malignancies. This report will review the preclinical and clinical results of the investigations with this exciting new therapeutic, its toxicities and future prospects.

Animals↗
PubMed2005

Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good?

The myelodysplastic syndromes (MDS) can be divided into "early" and "advanced" disease by evaluation of prognostic variables such as the number of cytopenias, karyotype, and percentage of myeloblasts. Patients with an isolated interstitial deletion of chromosome 5q31 represent a distinct subset who may derive particular benefit from immunomodulatory drugs. Goals of therapy for early MDS focus on hematologic improvement and maximizing quality of life. Thalidomide, the prototype of the immunomodulatory drugs, yields major erythroid responses in some patients with early MDS, but dose-limiting neurologic toxicities limit its potential clinical benefit. Lenalidomide, a more potent and non-neurotoxic derivative, has shown promising results in early MDS, yielding hematologic improvement in almost half of patients, and transfusion independence with cytogenetic remissions in approximately two thirds of patients harboring the chromosome 5q31 deletion.

Aged↗
PubMed2004

Histone deacetylase inhibitors in myelodysplastic syndrome.

Histone deacetylase (HDAC) inhibitors are amongst the newer therapies being introduced in refractory, relapsed, and resistant disease. These agents are mechanism-based and their use is targeted to the diseased cell or tissue. HDACs are key enzymes in the regulation of gene expression. They maintain a dynamic equilibrium in the acetylation state of highly conserved lysine residues on histones by which they regulate chromatin remodeling and gene expression. Changes in growth and differentiation leading to malignancy appear to occur by alterations in transcriptional control and gene silencing. Histone acetylation and DNA methylation have been implicated in these aberrant phenotypes. Inhibitors of DNA methylation such as 5-azacytidine or 5-azadeoxycytidine have been able to reverse DNA methylation patterns and have shown promise in patient studies. Similarly, HDAC inhibitors block deacetylation function, causing cell cycle arrest, differentiation, and/or apoptosis of many tumors. Several HDAC inhibitors have exhibited potent antitumor activity in human xenograft models, suggesting their usefulness as novel cancer therapeutic agents. Several are currently in phase I/II clinical trials both in hematological malignancies and in solid tumors. Agents used initially, such as phenylbutyrate, are effective in millimolar concentrations. Newer agents are being developed and these are effective at much lower concentrations and are relatively less toxic. In particular, hydroxamic acid-based polar compounds and cyclic tetrapeptides have shown activity against cancers at well-tolerated doses.

Antineoplastic Combined Chemotherapy Protocols↗