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PubMed2007

Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: A Hoosier Oncology Group Trial, HEM01-21.

Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2-27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8-10.9) and 13.2 months (95% CI 9.4-21.0), respectively. The median number of treatment cycles was seven (range 1-12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.

Administration, Oral↗
PubMed2004

Newer therapies for cutaneous sarcoidosis: the role of thalidomide and other agents.

Skin involvement occurs in a third of patients with sarcoidosis. The type of lesions can range from the transient erythema nodosum to the chronic facial lesion lupus pernio. For some patients with sarcoidosis, lesions on the face or elsewhere on the body may be the major or only indication for therapy. These lesions are often chronic and the use of corticosteroids may lead to more long-term complications. Conventional alternatives to corticosteroids include antimalarial agents, methotrexate, and azathioprine. Recently, several drugs have been studied for chronic cutaneous sarcoidosis; thalidomide has been the most widely used. Thalidomide has been demonstrated to suppress tumor necrosis factor (TNF) release, which may be important at both the initial and chronic phases of the inflammation of sarcoidosis and appears to be crucial as part of the initial granulomatous response. Thalidomide has a different toxicity profile than corticosteroids or immunosuppressives. The usual dosage has recently been investigated in a dose-escalation trial, with the majority of patients responding to 100 mg/day. Drug toxicity has been reported in the sarcoidosis trials. The most serious adverse effect has been peripheral neuropathy, which often resolves by reducing the dose or discontinuing the medication. Other drugs that have been studied for sarcoidosis include infliximab and tetracyclines. Infliximab is a chimeric monoclonal antibody against TNF, and several published reports have shown it to be effective for the treatment of cutaneous sarcoidosis. The efficacy of tetracyclines for cutaneous sarcoidosis could be on the basis of their immunologic properties. In addition, these drugs have potent antimicrobial activity against Propionibacterium acnes; there is increasing evidence to suggest this may be one of the causes of sarcoidosis. However, most of the newer agents for cutaneous sarcoidosis have only been studied in small series. Over the next few years, it is hoped that there will be clinical trials to determine the role of each new therapy in the treatment of cutaneous sarcoidosis.

Chronic Disease↗
PubMed2003

Thalidomide treatment for immunoglobulin D multiple myeloma in a patient on chronic hemodialysis.

A 64-year-old Japanese man suffering from IgD lambda myeloma and renal failure requiring chronic hemodialysis was treated with thalidomide. Serum IgD concentration was 4,050 mg/dl and myeloma cells constituted 95.6% of nucleated cells in bone marrow at the start of treatment. These parameters improved markedly to 1,590 mg/dl and 22.0%, respectively, in the 4 months immediately prior to his death due to pneumonia. Thalidomide caused peripheral neuropathy and constipation at a dose of 100 mg daily in the first week of treatment, but adverse effects resolved upon dose reduction. Thalidomide represents a valid therapeutic option for some myeloma patients receiving hemodialysis.

Humans↗
PubMed2003

Thalidomide derived immunomodulatory drugs (IMiDs) as potential therapeutic agents.

Thalidomide is known to be effective in the treatment of a number of conditions, including leprosy and various cancers. The exact mechanisms of action remain unclear although these are known to include anti-tumour necrosis factor (TNF)-alpha, T cell costimulatory, anti-angiogenic and anti-tumour activities. However, thalidomide is being superceded by novel structural derivatives which have been designed to have improved immunomodulatory activity and side effect profiles. These are currently being characterised and some are entering the clinic in phase I/II studies. One novel group of structural analogues are classified as the Immunomodulatory Drugs (IMiDs). This review describes the emerging immunological, anti-angiogenic and direct anti-tumour properties of thalidomide and the characterisation and clinical application of its IMiD analogues. We describe the laboratory studies which have led to the characterisation and development of IMiDs into potentially clinically relevant drugs. Early trial data suggests that these compounds may themselves become established therapies, particularly in certain cancers. Furthermore, ongoing studies will determine how best to apply these compounds to the appropriate clinical settings. We will describe the various clinical studies of lead compounds that are in progress and speculate as to the potential and future development of these exciting compounds.

Adjuvants, Immunologic↗
PubMed2006

The use of thalidomide in myeloma therapy as an effective anticancer drug.

Thalidomide and its immunomodulatory derivatives have provided the most significant advance in the therapy of myeloma since the introduction of high dose chemotherapy followed by stem cell transplantation nearly 20 years ago. The mechanism of action of thalidomide is complex and involves many aspects of malignant plasma cell growth and bone marrow stromal cell microenvironment interaction. Thalidomide was first used because of its anti-angiogenic properties, however it is the immunomodulatory actions that involve increasing host tumour-specific immunosurveillance by both T cell and natural killer cells which may be the most important mode of action.

Animals↗
PubMed2003

Thalidomide for the treatment of acute myeloid leukemia.

In analogy to solid neoplasms, accumulating data suggest the requirement of angiogenesis also for the development and progression of hematopoietic malignancies including acute myeloid leukemia (AML). Inhibition of increased microvessel density in bone marrow (BM) might be a promising target for pharmacological interventions aimed at reducing disease activity. Among the putative inhibitors of angiogenesis, thalidomide has demonstrated a considerable efficacy in myelodysplastic syndromes (MDS) and AML with overall response rates up to 56% and 25%, respectively. Responders experienced hematologic improvements with increased hemoglobin and platelet counts resulting in temporary transfusion independence. In AML, partial responses--defined as reduction of the leukemic blast cell infiltration of at least 50% in BM--occurred in four of 20 patients after one month of thalidomide administration in a previous phase I/II study. Additionally, we observed a long-term response in one AML patient of more than 20 months, meanwhile fulfilling the criteria of complete remission. The decrease in leukemic blast infiltration in BM of responders was accompanied by a significant reduction of the microvessel density. Overall adverse events caused by the drug consisted mainly of fatigue, constipation, skin rash and polyneuropathy with a tolerable dose of 200-400 mg p.o. per day. In conclusion, thalidomide as a single agent has significant anti-leukemic activity with some evidence for anti-angiogenic effects in BM, although the precise mechanism of action remains to be elucidated.

Acute Disease↗
PubMed2003

Poor tolerance to high doses of thalidomide in patients with primary systemic amyloidosis.

Treatments effective against multiple myeloma may be useful in primary systemic amyloidosis (AL). Thalidomide is active in myeloma. Results of the first 12 patients enrolled on a phase II trial of thalidomide for AL are presented. Progressive edema, cognitive difficulties, and constipation occurred in approximately 75%; dyspnea, dizziness and rash in 50%. Five developed progressive renal insufficiency. Deep venous thrombosis and syncope each occurred in two. Median time on the study was 72 days, range was 25 to 333 days. All 12 have withdrawn from the study (side-effects, 6; progression, 4; and death, 2 patients). AL patients do not tolerate high dose thalidomide.

Adult↗
PubMed2005

Effects of thalidomide on angiogenesis and tumor growth and metastasis of human hepatocellular carcinoma in nude mice.

AIM: To investigate the effects of thalidomide on angiogenesis, tumor growth and metastasis of hepatocellular carcinoma in nude mice. METHODS: Twenty-four nude mice were randomly divided into therapy group and control group, 12 mice in each group. Thalidomide dissolved in 0.5% sodium carboxyl methyl cellulose (CMC) suspension was administered intraperitoneally once a day at the dose of 200 mg/kg in therapy group, and an equivalent volume of 0.5% CMC in control group. Mice were sacrificed on the 30th d, tumor size and weight and metastases in liver and lungs were measured. CD34 and VEGF mRNA in tumor tissue were detected by immunohistochemistry and semi-quantitative RT-PCR respectively and microvessel density (MVD) was counted. Serum concentrations of TNF-alpha and ALT and AFP were also tested. RESULTS: MVD and VEGF mRNA in therapy group were less than those in control group (31.08+/-16.23 vessels/HP vs 80.00+/-26.27 vessels/HP, 0.0538+/-0.0165 vs 0.7373+/-0.1297, respectively, P<0.05). No statistical difference was observed in tumor size and weight and metastases in liver and lungs. TNF-alpha was significantly lower in therapy group than in control group (28.64+/-4.64 ng/L vs 42.69+/-6.99 ng/L, P<0.05). No statistical difference in ALT and AFP was observed between groups. CONCLUSION: Thalidomide can significantly inhibit angiogenesis and metastasis of hepatocellular carcinoma. It also has inhibitory effects on circulating TNF-alpha.

Angiogenesis Inhibitors↗
PubMed2003

Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis.

Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.

Adult↗
PubMed2003

Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma.

OBJECTIVE: To assess response rate, duration of response, progression-free survival, and toxicity of thalidomide in patients with relapsed multiple myeloma. PATIENTS AND METHODS: Thirty-two patients with relapsed multiple myeloma were entered into the study between April 29, 1999, and June 20, 2000. They were given oral thalidomide at a dosage of 200 mg/d for 2 weeks, which was then increased as tolerated to a maximum of 800 mg/d. The primary end point of the study was response rate. RESULTS: The median age of the patients was 67 years (range, 36-78 years). Prior chemotherapy had failed in all patients, and stem cell transplantation had failed in 5 patients (16%). There were 10 confirmed responses, yielding a response rate of 31%. In addition, there was 1 unconfirmed partial response and 7 minimal responses with no complete responses. The median duration of response was 11.9 months (range, 3.7-203 months). Overall, 20 patients have died, and 26 patients have experienced disease progression. The median follow-up of surviving patients was 28.5 months (range, 193-34.0 months), with a median progression-free survival of 8.6 months (95% confidence interval [CI], 4.7-16 months). The median progression-free survival among the responding patients was 15.7 months (95% CI, 8.6-25.6 months). The median overall survival for the entire group was 22 months (95% CI, 10.6-35.9 months). The most common treatment-related nonhematologic toxic effects (grade >3) were neuropathy (16%), sedation (13%), febrile neutropenia (6%), and constipation (6%). CONCLUSIONS: Thalidomide is useful in the treatment of patients with relapsed multiple myeloma and produced durable response in approximately one third of patients, with median response duration of nearly 1 year.

Adult↗
PubMed2004

Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases.

Inflammatory processes associated with the over-production of cytokines, particularly of TNF-alpha, accompany numerous neurodegenerative diseases, such as Alzheimer's disease, in addition to numerous systemic conditions, exemplified by rheumatoid arthritis and erythema nodosum leprosum (ENL). TNF-alpha has been validated as a drug target with Remicade and Enbrel available as prescription medications. Both, however, are large macromolecules, require injection and have limited brain access. The classical drug, thalidomide is being increasingly used in the clinical management of a wide spectrum of diseases. As its clinical value in treating ENL derives from its TNF-alpha inhibitory activity, thalidomide was chosen for structural modification for the discovery of novel and more potent isosteric analogues with appropriate lipophilicity to insure high brain penetration. TNF-alpha inhibitory activity was evaluated against lipopolysacharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in cell culture, whose viability was quantified to differentiate reductions in TNF-alpha secretion from that associated with cellular toxicity. Specific analogues potently inhibited TNF-alpha secretion, compared to thalidomide. This involved a post-transcriptional mechanism, as they decreased TNF-alpha mRNA stability via its 3'-untranslated region (UTR), as determined by luciferase activity in stably transfected cells with and without the 3'-UTR of human TNF-alpha.

Cells, Cultured↗
PubMed2000

Thalidomide: a comeback?

Thalidomide, a synthetic glutamic acid derivative first marketed in 1954 as a sedative, rapidly gained worldwide notoriety as a cause of phocomelia. To prevent further cases of this severe birth defect, thalidomide was removed from the market. Over the last few years, however, thalidomide has been found to exhibit properties of potential usefulness in a range of conditions. Trials are under way in rheumatic diseases, and safer analogs have been developed.

Contraindications↗
PubMed2000

Modulation of LPS-, PHA- and M. tuberculosis-mediated cytokine production by pentoxifylline and thalidomide.

Pentoxifylline and thalidomide have been used to downregulate the production of TNF-alpha in several disease entities including mycobacterial infections and autoimmune disorders. These drugs inhibit the production of TNF-alpha by different mechanisms, but little is known about possible synergism and modulation of other cytokines. Pentoxifylline and thalidomide inhibited the in vitro stimulated production of TNF-alpha, IL-1 beta and IFN-gamma in blood mononuclear cells. No significant modulation of antiinflammatory cytokines was found. When used together, these agents demonstrated additive inhibition, but no synergism. Modulation of cytokine response was similar when different stimuli were used, including M. tuberculosis in tuberculin-positive individuals. Therefore, the balance between efficacy and toxicity may be more favourable when pentoxifylline and thalidomide are used together instead of either drug alone. Clinical studies are needed to establish this advantage when anti-cytokine strategies are considered.

Cells, Cultured↗
PubMed2000

Thalidomide in solid tumors: the London experience.

Investigators at the Royal Marsden Hospital and University College in London have studied thalidomide (Thalomid) as both low-dose (100 mg orally, every night) and high-dose (600 mg, given as 300 mg twice per day) therapy for patients with a variety of solid tumors. In the phase II low-dose study, responses were disappointing in patients with melanoma, ovarian cancer, and breast cancer. Results for patients with renal-cell carcinoma were more encouraging. A case study of a patient with metastatic renal-cell carcinoma in the lung and lymph nodes in the low-dose thalidomide study illustrates that (1) responses may be very slow; (2) the palliative response is separate from the overall response, occurs much earlier, and is not consistent with an antiangiogenic action; and (3) peripheral neuropathy is a manageable side effect. Besides peripheral neuropathy, patients can experience severe constipation (even on low doses) as well as headache, edema, and skin rash for which treatment recommendations can be made. Anecdotal benefits of thalidomide include enhanced or maintained appetite, improved sleeping, and reduced sweating. The high-dose study has been submitted for publication.

Adult↗
PubMed2001

[The return of thalidomide].

Nearly four decades after its withdrawal from the marketplace because of the discover of its teratogenicity, the thalidomide is now attracting a renewed interest due to the identification of its important anti-inflammatory, immunomodulatory and anti-angiogenic effects. After the approval in the United States of the thalidomide for treatment of erythema nodosum leprosum, several studies have been conducted in patients with dermatologic disorders, conditions associated with HIV infection, graft-versus-host disease, rheumatoid arthritis, Cron's disease, and cancer. In this paper the mechanisms of action of thalidomide and its indications in human diseases are summarized.

Humans↗
PubMedDate not supplied

[Comparative treatment between thalidomide and transfer factor in severe atopic dermatitis].

AIMS: The atopic dermatitis is an chronic inflammatory illness of the skin. It exists an interrelation complex of factors gene, environmental, and psychological that contribute to the development and severity of the illness. The immunol aberrations significant is the answer increased of IgE specific antibodies toward antigens common, the liberation is increased of immunol mediators by the basophils and mast cells, eosinophils peripheral and local, besides enlarges the biphasic activity Th1/Th2 with liberation of cytokines (IL-4, IL-5, IL-13), GM-C5F, and decrease of IFN-gamma by the cells Th1. Leung to report a knowledge upon the bases immunopathologies of it atopic dermatitis has immunopathologies clinical important for the diagnosis and processing. Alternatives multiples of processing by the same complexity of the illness exist. OBJECTIVE: To compare the security and the clinical efficacy of the thalidomide and the factor of transfer in the atopic dermatitis severe. MATERIAL AND METHOD: Were studied patient with diagnosis of atopic dermatitis severe in agreement with the criterions of Hanifin and Rajka that they entered to the service of Allergy and Immunology Clinical of the Hospital Regional Lic. Adolfo López Mateos (public hospital). They were included 19 patient (women 12 and men 7, with age average 30 +/- 4 years). They were distributed in two groups. The first group of 5 patient administration thalidomide 200 mg/d during six months. The second group am administered the factor of transfer a total of 15 units by road oral during six months. Studies of laboratory for appraisal were requested immunology and metabolic pretreatment and pretreatment. RESULTS: In the group A dealt with thalidomide 5 patient and the group B dealt with FT, both presented a statistically significant decrease, as for the extension of the wounds (p < 0.01), and 1 am observed greater reduction in the intensity of the symptoms, the SCORAD total (p < 0.001 and p < 0.001 respectively) with statistical difference among them. None presented alterations immunologies and metabolic secondary to the use of the two drugs and not there was the need to suspend the processing. During the period of study, the patient were maintained controlled to the allergic rhinitis and the asthma. DISCUSSION: In the atopic dermatitis by its secondary clinical complexity to the multifactors etiologic, the alternatives of processing utilized in the present study are an option the security and efficacy, I am observed better clinical.

Adult↗
PubMed2001

Thalidomide: an old sedative-hypnotic with anticancer activity?

Thalidomide is a synthetic derivative of glutamic acid with sedative-hypnotic activity, which caused devastating teratogenic effects in the 1960s. This paper reviews the possible mechanisms of its teratogenic effect, its new therapeutic indications, the proposed mechanisms for its antitumor activity and, finally, reviews published studies of its application in oncology. Current data demonstrates that thalidomide is clinically promising in multiple myeloma, glioblastoma multiforme and renal cell cancer. Furthermore, a beneficial effect of the drug has been proposed in cancer-related cachexia, which merits further investigation. Well-designed, randomized studies are warranted to establish the possible indications of thalidomide as an antitumor compound.

Animals↗
PubMed2001

Thalidomide in refractory and relapsing multiple myeloma.

Patients with multiple myeloma (MM) refractory to chemotherapy can only benefit from supportive measures and have a very short survival. Thalidomide has recently shown antitumor activity in patients with refractory myeloma. Twenty-three patients (12 men and 11 women; median age, 72 years) with advanced MM were treated with thalidomide. Sixteen patients had refractory disease and seven had untested relapse. The median dose of thalidomide was 400 mg d (range, 200 to 800 mg/d). The drug was generally administered in two divided doses. Five patients required treatment discontinuation because of toxicity. Twelve of 23 patients (52%) responded. Three (13%) achieved a partial response, with greater than 50% reduction in serum monoclonal (M)-protein levels, and nine (39%) attained a minimal response, with a greater than 25% decrease in serum M-protein levels. No decrease in the size of soft tissue plasmacytomas was observed in six patients with extramedullary involvement.

Adult↗