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PubMed2005

Beneficial response to anakinra and thalidomide in Schnitzler's syndrome.

BACKGROUND: Schnitzler's syndrome is an inflammatory disorder characterised by chronic urticarial rash and monoclonal gammopathy, accompanied by periodic fever, arthralgia or arthritis, and bone pain. The cause and treatment are still unknown. OBJECTIVE: To assess treatment with thalidomide and an interleukin 1 receptor antagonist, anakinra, in Schnitzler's syndrome. CASE REPORTS: Three patients with Schnitzler's syndrome are described, one with IgM gammopathy, two with IgG type. In one patient, thalidomide induced complete remission, but was stopped because of polyneuropathy. Anakinra 100 mg daily in all three patients led to disappearance of fever and skin lesions within 24 hours. After a follow up of 6-18 months, all patients are free of symptoms. CONCLUSION: Anakinra proved to be effective in three patients with Schnitzler's syndrome. This treatment is preferable to thalidomide, which induced a complete remission in one of our patients, as it has fewer side effects.

Antirheumatic Agents↗
PubMed2002

Thalidomide: emerging role in cancer medicine.

Thalidomide--removed from widespread clinical use by 1962 because of severe teratogenicity--has antiangiogenic and immunomodulatory effects, including the inhibition of tumor necrosis alpha factor. It has now returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was approved by the U.S. Food and Drug Administration in 1998, and more recently certain malignancies, including multiple myeloma. Although thalidomide's mechanism of action remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials have confirmed benefit in relapsed disease, and the role of thalidomide in treating newly diagnosed patients is currently under study. Its use in other tumors is under evaluation, with promise in renal cell carcinoma, prostate cancer, glioma, and Kaposi's sarcoma. Activity has also been demonstrated in chronic graft-versus-host disease and in symptom relief as part of palliative care.

Adjuvants, Immunologic↗
PubMed2006

The thalidomide analogue, CC-4047, induces apoptosis signaling and growth arrest in childhood acute lymphoblastic leukemia cells in vitro and in vivo.

PURPOSE: Thalidomide and its analogues have shown promise in the treatment of multiple myeloma but their therapeutic potential has not been evaluated in models of acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: We assessed the effects of the thalidomide analogue, CC-4047, on the growth and apoptosis signaling of human B cell precursor (BCP) ALL cell lines and freshly obtained childhood BCP-ALL cells grown with or without stromal cells. In addition, we studied the effects of CC-4047 on the progression and dissemination of xenotransplanted human BCP-ALL cells in nonobese diabetic/severe combined immunodeficiency mice. RESULTS: CC-4047 reduced the proliferation of human BCP-ALL cell lines in vitro. In contrast with the antileukemic effect of cytarabin, this was more pronounced when cell lines or freshly obtained childhood BCP-ALL cells were cocultured with stromal cells. CC-4047 induced the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase in stroma-cocultured BCP-ALL cells. The inhibition of tumor growth, caspase-3 cleavage, and reduced microvessel density was observed in nonobese diabetic/severe combined immunodeficiency mice inoculated s.c. with childhood BCP-ALL cells upon CC-4047 treatment. After i.v. BCP-ALL xenotransplantation, CC-4047 reduced splenic dissemination. CONCLUSIONS: The thalidomide analogue, CC-4047, displays profound cytostatic effects on stroma-supported human ALL cells both in vitro and in vivo.

Animals↗
PubMedDate not supplied

Alterations of rat liver phospholipid composition induced by oral thalidomide.

In an attempt to elucidate the effects of oral thalidomide on liver phospholipid composition, doses of 1 and 3 mg/kg/day of thalidomide were orally administered to two groups of female Wistar rats (7 animals each), respectively, over a period of 60 days. Control animals (n = 7) received corresponding quantities of the vehicle alone. Chromatographic analysis and quantitative determination of the isolated phospholipid classes revealed statistically significant alterations of phospholipid fractions in the liver of the animals treated with the higher thalidomide dose (3 mg/kg/day). These alterations may be associated with changes in the metabolic activity, ionic transport and cell-cell interactions of the hepatic cellular components.

Administration, Oral↗
PubMedDate not supplied

Thalidomide effectiveness for bilateral chronic idiopathic anterior uveitis in a three-year-old child.

The authors report their experience with thalidomide in the treatment of a bilateral chronic idiopathic uveitis, in a 3-year-old female. This case was complicated by the presence of a cataract and an iris neovascularization in the right eye; furthermore it was partially unresponsive to a conventional anti-inflammatory and immunosuppressive therapy. Oral thalidomide induced slow but dramatic regression of the inflammation, and a significant reabsorption of neovascular tufts, both in slitlamp examination and on iris fluorescein angiography. The authors emphasize the efficacy of thalidomide as anti-inflammatory agent and as inhibitor of neoangiogenesis, reporting the recent literature about the use of this drug in ophthalmology.

Administration, Oral↗
PubMed2003

Thalidomide in refractory vulvar ulcerations associated with Crohn's disease.

We report a case of recurrent vulvar ulcerations developed on vegetations associated with Crohn's disease. Lesions responded to low-dose thalidomide treatment. A biopsy revealed a neutrophilic infiltrate with rare giant cells. Vulvar manifestations were consistent with metastatic Crohn's disease or with a reactive neutrophilic dermatitis. Thalidomide reduces the activity of tumor necrosis factor (TNF) alpha by accelerating the degradation of its mRNA. Nowadays, it has become a promising drug in a broad variety of disorders in which TNF-alpha seems to play a pivotal role, including inflammatory bowel diseases. This is the first case report presenting the efficacy of thalidomide in the treatment of vulvar involvement in Crohn's disease.

Adult↗
PubMed2004

Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide.

Langerhans cell histiocytosis (LCH) represents a group of rare histiocytic syndromes characterized by tissue infiltration with dendritic cells. The management of LCH is difficult as these disorders respond inconsistently to immunosuppressive and chemotherapeutic strategies. Thalidomide (N-phtalimidoglutarimide), initially used as a tranquilizer, has recently been used in the management of several inflammatory skin diseases. We describe the case of a 38-year-old male with mucocutaneous LCH. A treatment course with 6 cycles of 2-chlorodeoxyadenosin (cladribine) was initiated. This was well tolerated but withdrawn after 6 months to prevent secondary malignancy. A partial remission was seen. Subsequently, a treatment course with thalidomide 200 mg daily was started. This therapy resulted in a significant improvement of the mucocutaneous lesions within 4 weeks and complete healing was achieved after 3 months. Treatment was then successfully continued with daily doses of 100 mg to prevent relapse. In conclusion, thalidomide monotherapy represents an effective, safe and well-tolerated treatment option that should be considered as first-line therapy for mucocutaneous LCH.

Administration, Oral↗
PubMed2004

Hepatocellular carcinoma with intra-atrial tumor thrombi. A report of three cases responsive to thalidomide treatment and literature review.

BACKGROUND: In patients with advanced hepatocellular carcinoma (HCC), inferior vena cava/intra-right atrial (IVC/RA) tumor thrombi are not uncommon findings and are usually associated with extremely poor outcome. Surgical interventions as well as nonsurgical approaches, such as transcatheter arterial chemoembolization and radiotherapy, have been used in the treatment of patients with symptomatic IVC/RA tumor thrombi. However, such therapeutic modalities are usually not feasible when a patient shows poor general performance, the presence of metastatic disease, and underlying hepatic dysfunction. Such patients show limited survival. MATERIAL AND METHODS: Herein we describe 3 patients with advanced-stage HCC whose IVC/RA tumor thrombi and primary tumors regressed remarkably after low-dose thalidomide (200-400 mg/day) therapy. An Entrez PUBMED search of English Literature articles was performed to identify other cases of RA tumor thrombi in HCC who had received various treatments. RESULTS: Two of our patients survived for more than 15 months after the diagnosis of IVC/RA tumor thrombi, while the other had effective symptomatic palliation associated with a drastic fall of AFP serum levels and significant tumor regression within 4 weeks of thalidomide therapy. A literature review suggested that the survival of our patients is comparable with that of occasional patients who had received aggressive surgical intervention. CONCLUSIONS: Our results suggest that, despite the low tumor response rate in earlier studies, thalidomide therapy may sometimes provide effective palliation for patients with far advanced HCC with symptomatic IVC/RA tumor thrombi and who are not candidates for alternative treatment options.

Aged↗
PubMed1995

High-performance liquid chromatographic assay of plasma thalidomide: stabilization of specimens and determination of a tentative therapeutic range for chronic graft-versus-host disease.

Thalidomide is now widely used to treat chronic graft-versus-host disease, but its use is associated with non-teratogenic side effects such as peripheral neuropathy. To examine the value of monitoring plasma concentrations of the drug in such patients, we have developed a high-performance liquid chromatographic (HPLC) assay. The method uses 0.5 mL plasma, is linear to 10 mg/L and had a detection limit of 0.2 mg/L. Thalidomide in plasma specimens was unstable at physiological pH but could be stabilized for several weeks by simple acidification. We describe a protocol for monitoring patients treated with thalidomide which permits convenient transportation and storage of specimens and report, provisionally, that plasma concentrations in the range 1-7 mg/L are therapeutically effective in chronic graft-versus-host disease without adverse side effects.

Chromatography, High Pressure Liquid↗
PubMed2000

The redemption of thalidomide: standardizing the risk of birth defects.

In this paper we examine how a standardized drug distribution system contributed to a therapeutic and symbolic make-over of thalidomide. In the 1960s, thalidomide was seen as a horror drug that caused severe birth defects among over 10,000 babies who were exposed to it in utero. Currently, thalidomide is viewed as a potentially life-saving drug which is being distributed in the USA. We discuss this transformation from a social worlds perspective, showing how the standardized drug distribution system normalized the risk of foetal birth defects, while preserving the autonomy of health care professionals. The distribution system accomplished this transformation by focusing on the risk associated with female reproductive behavior, and by providing close reproductive surveillance of female patients. This standardized system solidified social inequalities and professional power relationships, revealing assumptions about trust, responsibility and risk.

Abnormalities, Drug-Induced↗
PubMed2006

Intractable intracranial tuberculous infection responsive to thalidomide: report of four cases.

Paradoxical enlargement and development of new intracranial tuberculomas and tuberculous brain abscesses on adequate antituberculosis treatment are well recognized and supposedly cytokine mediated. These lesions are often unresponsive to conventional antituberculosis treatment, corticosteroids, and surgery. We therefore assessed the effect of adjunctive thalidomide, a tumor necrosis factor alpha-modulating drug, in intractable intracranial tuberculosis that did not respond to standard medical and surgical therapy. Four consecutive children (three children with bacteriologic proof and one child with clinical evidence of intracranial tuberculosis) were studied. Three patients each had a giant tuberculous abscess, and the fourth had chronic basal arachnoiditis with progressive loss of vision. Three of the four patients had relentless neurologic deterioration, and all showed disease progression on neuroimaging despite full medical and appropriate surgical treatment. Marked clinical and neuroradiologic improvement occurred after thalidomide was added to the antituberculosis treatment regimen of these four patients. Adjunctive thalidomide might have a role in the management of intractable intracranial tuberculosis and needs further investigation in this regard.

Arachnoiditis↗
PubMedDate not supplied

Thalidomide: dual benefits in palliative medicine and oncology.

Thalidomide is an immunomodulator, anti-angiogenic agent, anti-cytokine, and anti-integrin. Alone or in combination with other drugs, thalidomide has also demonstrated anti-cachexin and anti-neoplastic properties. Anorexia and cachexia are common symptoms of advanced cancer. Since certain cytokines also promote tumor growth, we may have a class of agents with palliative and anti-tumor benefits in combination with anti-neoplastics and anti-cytokines, such as thalidomide.

Angiogenesis Inhibitors↗
PubMed1990

Thalidomide: treatment of severe recurrent aphthous stomatitis in patients with AIDS.

An increasing number of AIDS patients have been noted to suffer severe recurrent aphthous stomatitis (RAS), a condition often associated with high morbidity that remains unresponsive to conventional therapeutic interventions. In two cases thalidomide was administered to successfully treat AIDS patients with RAS. Both patients experienced complete abatement of pain shortly after therapy was initiated. Ulcerations that were present for months resolved after three or four weeks of thalidomide therapy without any adverse effects. Thalidomide appears to be an effective agent for the treatment of severe RAS unresponsive to traditional therapies.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma.

To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease.

Adult↗
PubMed2005

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1.

CC-4047, an immunomodulatory analog of thalidomide, inhibits multiple myeloma with unknown effects on the human osteoclast lineage. Early osteoclast progenitors are of hematopoietic origin and differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NFkappa-B ligand/macrophage colony-stimulating factor-stimulated bone marrow cell cultures. Treating bone marrow cultures with CC-4047 for 3 weeks decreased osteoclast formation accompanied by complete inhibition of bone resorption. The inhibitory effect was similar when cultures were treated for 3 weeks or for only the first week (90% inhibition), indicating that CC-4047 inhibits early stages of osteoclast formation. Inhibition of osteoclastogenesis by CC-4047 was mediated by a shift of lineage commitment to granulocyte colony-forming units at the expense of granulocyte-macrophage colony-forming units. Further studies revealed that this shift in lineage commitment was mediated through down-regulation of PU.1. Treatment with thalidomide resulted in significantly less potent inhibition of osteoclast formation and bone resorption. These results provide evidence that CC-4047 blocks osteoclast differentiation during early phases of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug for targeting both tumors and osteoclastic activity in patients with multiple myeloma and other diseases associated with osteolytic lesions.

Angiogenesis Inhibitors↗
PubMed2005

Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies.

Patients with myeloma, treated on the thalidomide arm of total therapy 2 (TT2), had a higher complete response (CR) rate and improved event-free survival (EFS) but not overall survival (OS). To evaluate the benefit of TT2's posttandem autotransplant consolidation chemotherapy and dexamethasone maintenance, outcomes were compared on TT2 without thalidomide (n = 345; median follow-up, 3.5 years) and on predecessor trial TT1 (n = 231; median follow-up, 11.5 years). CR rates were similar (43% vs 41%); however, 5-year estimates of continuous CR (45% vs 32%, P < .001) and 5-year EFS (43% vs 28%, P < .001) were superior with TT2, with a trend for improved OS (62% vs 57%; P = .11). OS was also superior among patients achieving CR and receiving the second transplantation early after the first transplantation. Superior EFS and OS with TT2 versus TT1 was noted in the two thirds presenting without cytogenetic abnormalities (CAs); 4-year posttandem transplantation OS for patients with CAs was 47% with TT1 and 76% with TT2 when combination chemotherapy rather than DEX was applied for consolidation (P = .040). Thus, TT2 (without thalidomide) improved OS of patients without CAs; those with CAs benefited from posttransplantation consolidation chemotherapy. The favorable effects of CR and rapidly sequenced second transplantation attest to the validity of a melphalan dose-response effect in myeloma.

Aged↗
PubMed2006

Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.

Newer chemotherapeutic protocols as well as high-dose chemotherapy have increased the response rate in myeloma. However, these treatments are not curative. Effective maintenance strategies are now required to prolong the duration of response. We conducted a randomized trial of maintenance treatment with thalidomide and pamidronate. Two months after high-dose therapy, 597 patients younger than age 65 years were randomly assigned to receive no maintenance (arm A), pamidronate (arm B), or pamidronate plus thalidomide (arm C). A complete or very good partial response was achieved by 55% of patients in arm A, 57% in arm B, and 67% in arm C (P = .03). The 3-year postrandomization probability of event-free survival was 36% in arm A, 37% in arm B, and 52% in arm C (P < .009). The 4-year postdiagnosis probability of survival was 77% in arm A, 74% in arm B, and 87% in arm C (P < .04). The proportion of patients who had skeletal events was 24% in arm A, 21% in arm B, and 18% in arm C (P = .4). Thalidomide is an effective maintenance therapy in patients with multiple myeloma. Maintenance treatment with pamidronate does not decrease the incidence of bone events.

Aged↗
PubMed2007

Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma.

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

Adult↗