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PubMed2002

Effect of thalidomide in patients with chronic heart failure.

BACKGROUND: Congestive heart failure (CHF) is characterized by enhanced immune activation, which possibly plays a pathogenic role in this disorder. We therefore examined whether immunomodulation with thalidomide could improve cardiac performance in patients with CHF. METHODS: Nine patients with chronic symptomatic CHF and left ventricular ejection fraction (LVEF) <40%, who were receiving "optimal" conventional cardiovascular treatment, were given 200 mg thalidomide daily in an open design for a period of 6 weeks. Tumor necrosis factor (TNF)-alpha and LVEF were measured at baseline and on completion of the study. RESULTS: Two patients withdrew because of side effects. Sedation was common and required dose reduction in 6 of 7 patients completing the study. Plasma levels of TNF-alpha were elevated at baseline compared with levels in healthy control patients, but decreased significantly from 33.9 +/- 10.1 pg/mL to 19.3 +/- 6.1 pg/mL during therapy (P <.05). LVEF increased in all patients from 26% +/- 9% to 34% +/- 10% at the end of the observation period (P <.05). CONCLUSIONS: In this pilot study, therapy with thalidomide in patients with CHF resulted in decreased TNF-alpha levels and increased cardiac performance. Although few patients were included, our results suggest that thalidomide should be further investigated as an immunomodulating agent in CHF.

Aged↗
PubMed2003

Thalidomide for the treatment of recalcitrant oral Crohn's disease and orofacial granulomatosis.

It has been suggested that thalidomide may be effective in the management of Crohn's disease, including the associated oral lesions. We detail the clinical response to low-dose thalidomide of 5 patients with clinical features of orofacial granulomatosis or oral Crohn's disease recalcitrant to recognized immunosuppressant therapy. All patients had clinical resolution of their symptoms and signs. Transient somnolence was the only reported adverse effect. Remission was maintained by extending the period between thalidomide doses. Thalidomide should be considered an effective therapy for the short-term treatment of severe orofacial granulomatosis in appropriately counseled patients.

Adolescent↗
PubMed1993

Thalidomide inhibits the replication of human immunodeficiency virus type 1.

Thalidomide, a selective inhibitor of tumor necrosis factor alpha (TNF-alpha) synthesis, suppresses the activation of latent human immunodeficiency virus type 1 (HIV-1) in a monocytoid (U1) line. The inhibition is dose dependent and occurs after exposure of the cells to recombinant TNF-alpha, phorbol myristate acetate, lipopolysaccharide, and other cytokine combinations. Associated with HIV-1 inhibition is a reduction in agonist-induced TNF-alpha protein and mRNA production. Thalidomide inhibition of virus replication in the phorbol myristate acetate- and recombinant TNF-alpha-stimulated T-cell line ACH-2 is not observed. The presence of thalidomide also inhibits the activation of virus in the peripheral blood mononuclear cells of 16 out of 17 patients with advanced HIV-1 infection and AIDS. These results suggest the use of thalidomide in a clinical setting to inhibit both virus replication and the TNF-alpha-induced systemic toxicity of HIV-1 and opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Effect of thalidomide on the expression of TNF-alpha m-RNA and synthesis of TNF-alpha in cells from leprosy patients with reversal reaction.

Hypersensitivity reactions called reversal reaction (RR) and erythema nodosum leprosum (ENL) occur in leprosy. They are characterized by an increase in tumor necrosis factor-alpha (TNF-alpha). Thalidomide is an effective treatment for ENL but not RR. Its effectiveness in ENL is attributed to inhibition of TNF-alpha, and this does not explain its failure to treat RR. We assessed thalidomide's effect on TNF-alpha in RR. Mononuclear cells from RR and non-RR patients and healthy individuals were treated with thalidomide and M.leprae (AFB), a cytosol fraction of M. leprae or Dharmendra lepromin. Thalidomide suppressed TNF-alpha, but when some RR patients' cells were stimulated with AFB, it enhanced TNF-alpha.

Adolescent↗
PubMed2002

BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenström's macroglobulinemia.

Multiple myeloma remains incurable. Despite the pursuit of various chemotherapeutic approaches, little improvement in outcome has been made in the last 30 years. Thalidomide, dexamethasone, and clarithromycin are oral, nonmyelosuppressive agents, each with reported single agent activity against myeloma. We evaluated a regimen of clarithromycin (Biaxin), low-dose thalidomide and dexamethasone (BLT-D) in patients with previously untreated or treated multiple myeloma or Waldenström's macroglobulinemia. Patients were initially given clarithromycin 500 mg twice daily, thalidomide 50-200 mg daily, and dexamethasone 40 mg weekly until disease progression. Minimum response was defined as > 50% reduction in monoclonal immunoglobulin or light chain levels in serum or urine. Response, toxicity, and survival were determined on an evaluable and/or intent-to-treat basis. Of the 50 patients available for analysis, 92% remain alive and 64% remain on treatment with a median and mean duration of treatment of 7 and 8 months, respectively. Overall, 93% of evaluable patients responded to BLT-D, including 13% complete remissions, 40% near complete responses, 13% major responses, and 27% partial responses. Minimal drug resistance was initially encountered. Neurotoxicity, although usually mild to moderate, was the primary reason for treatment discontinuation. Only four patients died, including three sudden deaths in patients with severe cardiopulmonary disease. It appears that BLT-D is a highly effective, nonmyelosuppressive regimen for myeloma. Caution should be exercised when using thalidomide, alone or in combination, in patients with a preexisting tendency to thromboses, severe cardiopulmonary disease, or neurologic dysfunction.

Aged↗
PubMed2002

Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies.

Trials to determine the effect of thalidomide in patients with Myelofibrosis with Myeloid Metaplasia (MMM) have produced inconclusive results due to different criteria for response and heterogeneous study participants. We undertook a pooled-analysis to assess the effects of such treatment on a larger series of cases and with a uniform assessment of response. We used updated data on 62 individual patients from 5 phase II trials that evaluated thalidomide therapy in MMM patients. Responsewas judged on individual disease parameters, on the improvement of the Dupriez risk categories and on the improvement of a 6 point "severity score" based on myeloproliferative and myelodepletive indexes of the disease. Overall, using standard dose of thalidomide, i.e. starting with no less than 100 mg/day, 49 patients (79%) had more than 4 weeks of therapy. Twenty-nine percent of patients with moderate to severe anemia showed an increase in hemoglobin or reduction/abolishment of blood transfusion requirements, 38% with moderate to severe thrombocytopenia had an increase in platelet counts, and 41% with high grade splenomegaly demonstrated a measurable reduction in splenic size. These effects led to an absolute decrease in the "severity" score in 44.9% of the patients. Major disease severity and high degrees of splenomegaly before therapy predicted response with a probability of 61.9%. However, worsening of the "severity" score was observed in 20.4% of the patients, 18% having a "myeloproliferative reaction" with leukocytosis and/or thrombocytosis. Sixty-six percent of the patients discontinued the drug before 6 months of treatment due to intolerance. In conclusion, there is a small but clear improvement of disease severity with thalidomide therapy in MMM. The potential for myeloproliferative reactions and the unfavorable dose-related toxicity profile argue for future studies using lower doses of this drug.

Adult↗
PubMed2004

Aminoglycoside-associated severe renal failure in patients with multiple myeloma treated with thalidomide.

Thalidomide has been proved to play an important role in rescue treatment of patients with refractory/relapsed multiple myeloma (MM). However, thalidomide therapy is associated with numerous side effects, mainly somnolence, constipation, fatigue or peripheral neuropathy. We report three patients diagnosed with MM and treated with thalidomide as salvage therapy who developed severe renal failure when they received aminoglycoside antibiotics. This observation suggests that thalidomide can potentiate nephrotoxicity of aminoglycoside antibiotics in patients with MM.

Aged↗
PubMed2005

Combination of bortezomib, thalidomide, and dexamethasone in the treatment of relapsed, refractory IgD multiple myeloma.

The use of the proteasome inhibitor bortezomib has been recently introduced into the treatment of relapsed, refractory multiple myeloma (MM). We here demonstrate a case of a patient with IgD MM who was successfully treated with a combination of bortezomib, thalidomide, and dexamethasone. Relapse of the disease occurred following tandem autologous transplantation and was refractory to a salvage therapy consisting of thalidomide, cyclophosphamide, etoposide, and dexamethasone. While the administration of thalidomide was continued, the addition of bortezomib and dexamethasone led to a complete remission after 2 cycles of therapy. The feasibility of this treatment is supported by a recently reported phase I/II trial that used a lower dose of thalidomide in combination with an equal dose of bortezomib. This is the first report of a patient with IgD MM treated accordingly, suggesting that this entity is highly sensitive to the novel therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset.

The efficacy of thalidomide (alpha-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor alpha. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2-mediated T cell proliferation and interferon gamma production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.

Antibodies, Monoclonal↗
PubMed2002

Phase II trial of thalidomide in renal-cell carcinoma.

BACKGROUND: Thalidomide has been reported to yield anti-tumor activity in cancer. We performed a phase II trial of this drug in patients with metastatic renal cell carcinoma to determine its efficacy. PATIENTS AND METHODS: Patients with proven metastatic renal cell cancer, measurable progressive disease and a performance status of 0-2 were enrolled in this study. Thalidomide was given daily at a starting dose of 400 mg, followed by a 400 mg increment to 800 mg and then to 1200 mg with 6-12 weeks at each dose level. The response rate at 6 months was the primary end point. Toxicity, overall survival, tumor vascularization depicted on color Doppler ultrasonography and serum vascular endothelial growth factor, basic fibroblast growth factor, interleukin-12 and tumor necrosis factor-alpha levels were secondary end points. RESULTS: Forty patients were enrolled. Two partial responses were observed (5%) and disease remained stable in nine patients after 6 months. Median survival was 10 months. Toxicity was high, with frequent manifestations of fatigue, constipation and lethargy. The incidence of neuropathy detected on electromyography (EMG) attained 70% at 6 months, and 100% in patients on thalidomide for 12 months. Nine patients developed venous thromboembolism during the first 12 weeks of treatment, and three of them experienced pulmonary embolism. One unexpected (and unexplained) death occurred. CONCLUSIONS: Despite undisputed, albeit marginal, activity in renal cell cancer, high-dose thalidomide cannot be recommended using this schedule since the level of toxicity is high.

Adult↗
PubMed2004

Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study.

BACKGROUND: High-dose chemotherapy with autologous stem cell transplantation after initial cytoreductive chemotherapy with the combination vincristine, doxorubicin and dexamethasone (VAD) is considered an effective therapy for many patients with newly diagnosed, symptomatic multiple myeloma. Response to initial cytoreductive chemotherapy is important for the long-term outcome of such patients. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of a liposomal doxorubicin-containing VAD regimen with thalidomide, administered on an outpatient basis, as initial cytoreductive treatment in previously untreated patients with symptomatic myeloma. PATIENTS AND METHODS: Thirty-nine myeloma patients were treated with vincristine 2 mg intravenously (i.v.), liposomal doxorubicin 40 mg/m(2) i.v. administered as single dose on day 1, and dexamethasone 40 mg per os daily for 4 days. Dexamethasone was also given on days 15-18 of the first cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after four cycles of treatment. After completion of four cycles, the patients were allowed to proceed to high-dose chemotherapy or to receive two additional cycles of the same treatment. RESULTS: On an intention-to-treat basis, 29 of the 39 patients (74%) responded to treatment. Four patients (10%) achieved complete and 25 (64%) partial response. Three patients (8%) showed minor response and seven (18%) were rated as non-responders. Major grade 3 or 4 toxicities consisted of neutropenia (15%), thrombocytopenia (15%), deep vein thrombosis (10%), constipation (10%), skin rash (5%) and peripheral neuropathy (5%). Two patients (5%) experienced early death due to infection. CONCLUSIONS: The combination of vincristine, liposomal doxorubicin, and dexamethasone (VAD doxil) with thalidomide is an effective and relatively well-tolerated initial cytoreductive treatment. Prospective randomized studies are required in order to assess the effect of this regimen on the long-term outcome of patients with multiple myeloma.

Adult↗
PubMed2006

Results of three-dimensional conformal radiotherapy and thalidomide for advanced hepatocellular carcinoma.

PURPOSE: To evaluate the effectiveness of three-dimensional conformal radiotherapy and thalidomide in the treatment of advanced hepatocellular carcinoma. METHODS: Between 1999 and 2003, 121 patients (mean age, 54.4 +/- 12.4 years; range, 20-81 years) with advanced hepatocellular carcinoma received three-dimensional conformal radiotherapy and thalidomide. Radiation was delivered in 1.5 Gy fractions twice daily for 5 days a week, for a total dose of 45-75 Gy. Mean treatment volume was 429.52 +/- 408.50 cm(3) (range, 26.89-2284.82 cm(3)). Thalidomide was given concomitantly: 200 mg/day in 109 patients, 300 mg/day in 8 patients and 400 mg/day in 4 patients. Treatment responses, survival rates and factors affecting survival were analyzed. RESULTS: Treatment responses were observed in 61% of the patients. Liver cirrhosis (P = 0.001) and tumor size (P = 0.001) significantly affected the tumor responses. Overall survival at 6, 12 and 24 months was 84.8, 60.0 and 44.6%, respectively. On univariate analysis, liver cirrhosis (P = 0.003), Karnofsky performance status (P = 0.007), tumor size (P < 0.001), portal vein tumor thrombosis (P < 0.001) and alpha-fetoprotein level (P = 0.003) were shown to significantly affect survival. On multivariate analysis, only thrombosis (P = 0.039) and alpha-fetoprotein level (P = 0.006) were shown to be factors affecting survival. CONCLUSIONS: Three-dimensional conformal radiotherapy with thalidomide seems to be effective in the treatment of advanced hepatocellular carcinoma.

Adult↗
PubMed2001

Behçet's disease in UK children: clinical features and treatment including thalidomide.

OBJECTIVE: To study the clinical spectrum of Behçet's disease (BD) in childhood, and to report our experience of using thalidomide. METHOD: Ten children, diagnosed with BD, were studied retrospectively. RESULTS: The median (range) age at first presentation was 4 (1.2-12.0) yr, at diagnosis was 11 (3-15) yr and the follow-up period was 4.1 (0.6-6.3) yr. Oral ulcers were present in all patients (100%), genital ulcers were present in six (60%), peri-anal ulcers were present in three (30%), skin manifestations were present in nine (90%), intracranial hypertension was present in two (20%), mild gastrointestinal symptoms were present in five (50%), joint symptoms were present in six (60%), ocular lesions were present in five (50%), but only one child had anterior and posterior uveitis. Therapeutically, a range of drugs was used, including colchicine, that resulted in good responses in five children. Thalidomide (1 mg/kg/week to 1 mg/kg/day) was used in five children who were unresponsive to other immunosuppressive agents. It resulted in complete remission in three children and less frequent milder oral ulcers in two. Neuropathy developed in two children and in one it was irreversible. CONCLUSION: BD in children is similar to the disease in adults. Thalidomide provided a useful therapeutic option for severe oral and genital ulceration which was unresponsive to other therapies. Awareness of the danger of axonal neuropathy and teratogenesis at all times during thalidomide therapy is crucial. A low dose is probably as effective as higher doses.

Adolescent↗
PubMed1999

Thalidomide increases both REM and stage 3-4 sleep in human adults: a preliminary study.

Polysomnography was used to assess the effect of thalidomide on human sleep. This compound significantly increased the time spent in REM and stage 3-4 sleep as compared with placebo. On the other hand, thalidomide significantly decreased the time spent in stage 1, while the time spent in stage 2 was unchanged. The effect of thalidomide on REM and stage 3-4 sleep is unique as compared with other hypnotics. Although the mode of action of this compound is unknown, further studies on thalidomide should help in our understanding of the mechanisms of sleep regulation.

Adult↗
PubMed2000

Current role of thalidomide in cancer treatment.

Thalidomide (Thalidomid, Celgene, Warren, NJ) is a putative anti-angiogenesis and immunomodulatory agent that has demonstrated activity in various dermatologic and rheumatologic conditions in addition to Crohn's disease. The biologic effects of thalidomide and the clinical trials conducted in solid tumors, hematologic malignancies, chronic graft-versus-host disease (GVHD), and cancer-related cachexia are reviewed. A summary of the preliminary results of ongoing clinical trials is presented, and the future directions of thalidomide research in the oncology are discussed.

Angiogenesis Inhibitors↗
PubMed2002

Thalidomide and immunomodulatory drugs as cancer therapy.

The demonstration of increased angiogenesis in cancer pathogenesis prompted the use of thalidomide in both solid tumors and hematologic malignancies. Its broad spectrum of actions besides its antiangiogenic potential, specifically, its immunomodulatory properties, antiinflammatory actions, and direct effect on tumor cells and their microenvironment, provides an alternative strategy in the armamentarium against cancer. Thalidomide is being evaluated for treatment of hematologic cancers like multiple myeloma and myelodysplasia, and solid tumors like lung, breast, renal, and colon cancer. Thalidomide analogues, the immunomodulatory drugs have increased potency and have demonstrated efficacy and reduced toxicity in phase I and II clinical studies. This article reviews both laboratory-based and clinical studies with thalidomide and the immunomodulatory drugs and their application in different cancers.

Adjuvants, Immunologic↗
PubMedDate not supplied

Thalidomide is inactive in heavily pretreated patients with metastatic breast cancer.

Experimental studies have demonstrated that thalidomide has anti-tumor activity mediated by blockage of angiogenesis, with clinical efficacy in multiple myeloma, glioblastoma multiforme, and renal cell cancer. We investigated the therapeutic activity and toxicity of thalidomide in patients with progressive metastatic breast cancer pretreated with chemotherapy. Inclusion criteria were metastatic breast cancer in progression of disease after at least two lines of chemotherapy, age > or = 18 years, performance status < or = 2, and adequate hematologic, renal, and hepatic functions. Twelve patients entered the study, eight of whom were pretreated with three or more lines of chemotherapy (66.7%). Thalidomide was well tolerated: the most common side effects were constipation and somnolence (58.3% of patients). No objective response or durable stable disease was observed. Median time to progression and median overall survival were 8 weeks (range, 4-10 weeks) and 16 weeks (range, 8-54 weeks), respectively. In conclusion, thalidomide is an ineffective treatment in patients with progressive metastatic breast cancer heavily pretreated with chemotherapy.

Adult↗
PubMed2006

The combination of capecitabine and thalidomide in previously treated, refractory metastatic colorectal cancer.

BACKGROUND: With the increasing survival of patients with metastatic colorectal cancer (CRC) there is a growing need for effective second- and third-line agents. We conducted a multicenter, phase II study to examine the combination of capecitabine and thalidomide (Cape/Thal) in patients with refractory metastatic CRC. METHODS: Patients with previously treated stage IV CRC were eligible. Treatment consisted of capecitabine at 1,000 mg/m2 po BID for 14 days every 3 weeks and thalidomide, starting at 200 mg po QD continuously. Thalidomide was escalated individually to 600 mg po QD as tolerated. We analyzed overall survival (OS), progression-free survival, response, and toxicity rates. RESULTS: Thirty-four eligible patients were enrolled. The median age was 57 years, and most patients had a normal performance status (65%). All patients had received prior chemotherapy and 19 (56%) had received 2 or 3 prior regimens. The median number of Cape/Thal cycles administered was 3 (range, 1-15). Grade 3/4 toxicities included fatigue (15%), venous thromboembolic events (12%), somnolence (12%), and constipation (9%). Grade 2 hand-foot syndrome occurred in 5 (15%) patients. There were no radiographic responses; 13 patients (38%) achieved stable disease. The median PFS was 2.6 months (95% confidence interval [CI] = 2.2-3.9) and the median OS was 7.1 month (95% CI = 5.2-12.0). CONCLUSIONS: Though well-tolerated, the combination of capecitabine and thalidomide was not associated with objective tumor responses in a population of patients with previously treated metastatic CRC.

Administration, Oral↗