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PubMed1997

Effect of thalidomide on apoptosis of lymphocytes and neutrophils.

Thalidomide causes congenital anomalies and it is immunomodulatory. These properties could be explained by an ability to alter the orderly process of programmed cell death during embryogenesis and modulation of apoptosis of lymphoid and/or myeloid cells in the immune response. Apoptosis of lymphoid and myeloid cells was studied by measuring the percentage of cells capable of excluding propidium iodide and expressing phosphatidylserine on their outer membrane. In addition, expression of Fc gamma RIII (CD16) was used to assess neutrophil apoptosis. Thalidomide did not affect the rate of apoptosis of CTLL-2 cells deprived of, or supplemented with, IL-2; of T-cells (mitogen-stimulated or resting) or of neutrophils. However, neutrophils obtained from HIV-infected patients treated with thalidomide showed reduced expression of CD16, a surrogate marker for apoptosis of neutrophils. Thalidomide's effect on neutrophil apoptosis in vivo warrants further investigation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma.

We report two patients who were treated with thalidomide for resistant multiple myeloma (MM) and developed extramedullary plasmacytomas despite a good response in the bone marrow. The first patient had progressive disease 18 months post autologous peripheral stem cell transplant. Two and a half months after the initiation of thalidomide therapy extensive new plasmacytomas of the skin and nasal mucosa appeared while the medullary response continued. The second patient was treated with thalidomide for resistant MM. Despite a medullary response he developed neurological signs compatible with cranial nerve involvement and an MRI study was suggestive of a plasmacytoma involving the sellar region. We assume that a change in the expression of some adhesion molecules on the myeloma and/or the stromal cells is responsible for this phenomenon. Treating Physicians should be aware of this phenomenon in MM patients receiving thalidomide.

Adult↗
PubMed2004

Thalidomide and analogues: current proposed mechanisms and therapeutic usage.

Microvessel density is a prognostic factor for many cancers, including prostate. For this reason, several studies and therapeutic approaches that target the tumor microvasculature have been attempted. Thalidomide has long been recognized as an antiangiogenic molecule. Recently, this drug has regained favor as an anticancer agent and is in clinical trial for multiple myeloma and prostate cancer, among others. This article will briefly review the proposed mechanisms of action for thalidomide, discuss why these activities are of therapeutic value in diseases currently undergoing clinical trials, and summarize the current status of clinical trials for prostate cancer. The focus will be predominantly on the relationship of thalidomide to angiogenesis, as well as on the future and potential value of thalidomide-inspired structural derivatives.

Angiogenesis Inhibitors↗
PubMed2003

Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.

Thalidomide has antiangiogenic properties and was found to be effective in patients with multiple myeloma (MM) when used in the setting of posttransplantation relapse. We have now analyzed risk factors associated with development of deep vein thrombosis (DVT) in a cohort of 535 patients treated with thalidomide with cytotoxic chemotherapy (VAD [vincristine/doxorubicin/dexamethasone], CAD [cyclophosphamide/doxorubicin/dexamethasone], DCEP [dexamethasone/cyclophosphamide/etoposide/cisplatin], or DT-PACE [dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide] or without cytotoxic chemotherapy (thalidomide and dexamethasone only). A total of 82 patients developed DVT, and the frequency was affected by a number of baseline characteristics. On multivariate analysis, the combination of thalidomide with chemotherapy including doxorubicin was associated with the highest odds ratio (OR) for DVT (4.3; P < or = 0.001); in addition, newly diagnosed disease (OR, 2.5; P = 0.001) and chromosome 11 abnormality (OR, 1.8; P = 0.048) were also independent predictors for DVT. With a median follow-up of 2.9 years, survival was inferior in patients with chromosome 13 abnormalities (P = 0.001), age > 60 years (P = 0.001), lactate dehydrogenase level > or = 190 IU/L (P = 0.002), and creatinine level > or = 2 mg/dL (P < 0.001). However, the development of DVT did not adversely affect survival when examined as a time-dependent variable and adjusted for standard risk features (hazard ratio, 0.8; P = 0.162).

Aged↗
PubMed2004

Acute exacerbation of chronic hepatitis B during thalidomide therapy for multiple myeloma: a case report.

We report a case of acute fatal exacerbation of chronic hepatitis B in a 50-year-old man with multiple myeloma being treated with thalidomide. The patient had a medical history of chronic hepatitis B and was diagnosed with stage IIIA multiple myeloma. He suffered two episodes of transient transaminitis of unknown origin after successive autologous stem cell transplantations. Spontaneous resolutions of the transaminitis were observed without special management. At that time, PCR of hepatitis B virus (HBV) were all-negative. After 5-months' administration of thalidomide for the second relapse of the multiple myeloma, he suddenly experienced dizziness and jaundice. The level of HBV DNA was 1,641 pg/mL and the serologic tests for other viruses were negative. Despite conventional supportive care, he expired due to septic shock caused by Klebsiella pneumonia. Based on the stable disease status of the multiple myeloma and exclusion of other hepatotoxic agents, it was assumed that the exacerbation of the hepatitis B virus during the thalidomide therapy preceded the bacterial sepsis. With the increased use of thalidomide in cancer treatment, cautious monitoring of the viral burden should be performed in patients with chronic hepatitis B.

Angiogenesis Inhibitors↗
PubMed2006

Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma.

OBJECTIVE: To evaluate the efficacy and safety of adding thalidomide to the pegylated liposomal doxorubicin, vincristine, and decreased-frequency dexamethasone (DVd) regimen for multiple myeloma. PATIENTS AND METHODS: Patients newly diagnosed as having active multiple myeloma and those with relapsed-refractory disease were studied between August 2001 and October 2003. Patients received DVd as previously described. Thalidomide was given at 50 mg/d orally and the dose increased slowly to a maximum of 400 mg/d. At the time of best response, patients received maintenance prednisone, 50 mg orally every other day, and daily thalidomide at the maximum tolerated dose for each patient. The primary end point was the rate of complete responses plus very good partial responses as defined by the European Group for Blood and Marrow Transplantation criteria and the Intergroupe Français du Myélome, respectively. RESULTS: Of 102 eligible patients, 53 were newly diagnosed as having multiple myeloma, and 49 had been previously treated for multiple myeloma. The complete response plus very good partial response rate was 49% and 45%, with an overall response rate of 87% and 90% for patients with newly diagnosed and previously treated multiple myeloma, respectively. Furthermore, better responses were associated with improved progression-free and overall survival. The most common grade 3 and 4 adverse events were thromboembolic events (25%), peripheral neuropathy (22%), and neutropenia (14%). CONCLUSIONS: The addition of thalidomide to the DVd regimen significantly improves the response rate and quality of responses compared with the DVd regimen alone. This improvement is associated with longer progression-free and overall survival. The rate of observed quality responses is comparable to responses seen with high-dose therapy.

Aged↗
PubMedDate not supplied

Use of simple hematological, biochemical and clinical parameters to monitor response of multiple myeloma patients on high dose thalidomide therapy.

BACKGROUND: Evidence of increased bone marrow vascularity in multiple myeloma (MM) has led to the use of anti-angiogenic drugs especially thalidomide in relapsed or refractory patients. Currently, parameters such as serum/ urine electrophoresis for M (monoclonal) proteins, bone marrow biopsy with touch preparation and b2 microglobulin are routinely used to assess response to therapy. These investigations are expensive, invasive and require high technical setup. AIM: To correlate simple and routine hematological and biochemical parameters with the key marker of disease i.e. M proteins. SETTINGS AND DESIGN: This is an open label, uncontrolled, single-arm study. MATERIALS AND METHODS: Twenty nine refractory or relapsed multiple myeloma patients of both sexes (M=20, F=9) with age ranging between 35-72 years were initiated on 200 mg/day of thalidomide with fortnightly increments of 200 mg to a maximum tolerated dose not exceeding 800 mg/day. All hematological and biochemical parameters were monitored at monthly intervals for one year. STATISTICAL ANALYSIS: Correlation analysis was performed between hemoglobin (Hb), total leukocyte count (TLC), absolute neutrophil count (ANC), platelet count (PC), total proteins (TP), serum albumin and serum globulin on one hand and M protein levels on the other using Pearsons Correlation test by SPSS version 7.5. RESULT: Hb, TLC, ANC, PC and serum albumin levels showed a significant negative correlation with M proteins. A highly significant positive correlation existed between M proteins on one hand and TP and globulin levels on the other. Dryness of skin indicated positive response to therapy. These correlations were found to be significant at the end of one month of therapy in all the above-mentioned parameters except in TLC where it was significant after 2 months of thalidomide therapy. CONCLUSION: Results suggest that sustained efficacy of thalidomide therapy may be amenable to monitoring by these simple, inexpensive and easily available investigations after ascertaining an initial response by M protein and marrow plasmacytosis as these parameters closely follow M protein levels. However more studies are required to further substantiate these findings.

Adult↗
PubMed2003

Thalidomide: from tragedy to promise.

Thalidomide is an immunomodulatory and antiangiogenic drug. Although the exact mechanism of action is not fully understood, it has been shown to be active in a variety of diseases. There are multiple trials going on to evaluate the optimal dose of thalidomide and the importance of combining thalidomide with other drugs. This review introduces the properties and putative mechanism of action of thalidomide and summarizes the most important clinical trials with this biological modifier.

Angiogenesis Inhibitors↗
PubMed1992

Thalidomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood.

Thalidomide is well documented as being an effective drug in the treatment of erythema nodosum leprosum (ENL). The mechanism of action of thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully determined. Lepromatous leprosy patients experiencing ENL have been reported to have an increase in the ratio of CD4+ to CD8+ cells in their blood and ENL skin lesions. Thalidomide has been shown to cause a decrease in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males. This decrease was due to a significant reduction in the numbers of Cd4+ lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In this study, thalidomide's effectiveness in halting chronic ENL and arresting a relapse into ENL was consistently associated with a decrease in the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy patients.

Adult↗
PubMed1998

Paclitaxel is more effective than thalidomide in inhibiting LNCaP tumor growth in a prostate cancer model.

LNCaP tumors were treated by either administration of paclitaxel, thalidomide or by orchiectomy in order to determine their relationship with markers pertaining to the process of tumor growth, apoptosis or angiogenesis. Forty rats bearing LNCaP tumors were divided into 4 groups of 10 and treated by either paclitaxel (20 mg/kg x 5 days); thalidomide (200 mg/kg x 5 days/week x 5 weeks); or orchiectomy. After 6 weeks serum samples were removed for PSA determination and the animals sacrificed for evaluation of: A) tumor volume; B) tissue bcl-2, cyclin D, PSA and factor VIII immunohistochemically graded (0-5 scale) for marker expression; and C) serum PSA. Comparisons were made to untreated LNCaP tumors. Statistically significant differences were determined using the nonparametric Mann-Whitney test. Paclitaxel produced significant differences in volume (p < 0.001), expression of bcl-2 (p < 0.043), cyclin D (p < 0.023), tissue PSA (p < 0.001) and serum PSA (p < 0.019) levels. Thalidomide altered expression of bcl-2 (p < 0.011) and tissue PSA (p < 0.002). Orchiectomy altered volume (p < 0.002) and bcl-2 expression (p < 0.001). All three therapies have been suggested for prostate cancer and each produced alterations in accepted markers for treatment response (either reduced volume or serum PSA). Paclitaxel significantly influenced the most markers. Of interest was that all treatments, especially thalidomide, a known antiangiogenesis agent, reduced factor VIII, although not significantly. Evidently each treatment evokes different pathways of activity.

Androgen Antagonists↗
PubMed1998

[Thalidomide once more in the spotlight].

Thalidomide was withdrawn from the market in the early sixties because of major teratogenic effects such as reduction defects of the limbs. Since, however, it has been found to be an effective drug in erythema nodosum leprosum. In the United States it was decided in September 1997 to admit thalidomide to the market for this indication, and in South America it has been available for this indication all the time. Thalidomide is also efficacious in other major disorders (e.g. aphtae and ulcers in aids) or its efficacy is being investigated in clinical trials (e.g. autoimmune diseases, other complications in aids). The American Food and Drug Administration has imposed conditions for the use of thalidomide. Users have to sign an informed consent and to take adequate contraceptive measures. Physicians should inform the patients and monitor side effects. Pharmacists should record and control the use.

Adult↗
PubMed1976

[Genital malformations in thalidomide-damaged girls (author's transl)].

Due to the close morphological relationships and the dependence of the genital system on inductive impulses from the uropoietic system, the possibility of an increased incidence of malformations in the area of the female genitals for thalidomide-damaged children is to be expected. This suspicion is supported by the accumulation of reports of genital malformations in deceased children from mothers who took thalidomide-containing medicaments during the early weeks of pregnancy. - A 14-year-old patient with malformations of both upper extremities whose mother had taken thalidomide during the 6th to the 9th week of pregnancy presented at our hospital with complaints of cyclic pain in the lower abdomen. Although the ovaries and fallopian tubes were normally developed, the uterus and the vagina were absent in this patient. After this manuscript had been completed, we heard of 3 additional cases of genital malformation with a known thalidomide anamnesis.

Abnormalities, Drug-Induced↗
PubMed1999

Thalidomide in the treatment of refractory rheumatoid arthritis.

OBJECTIVE: To review outcomes in 10 patients with rheumatoid arthritis (RA) treated with thalidomide. METHODS: We reviewed our experience with 10 patients treated with thalidomide using a standard therapeutic protocol and standard outcome measures. RESULTS: We observed no significant improvement in any outcome measure, likely as a consequence of the limited duration of therapy related to thalidomide toxicity. CONCLUSION: Formal studies of the efficacy of thalidomide in RA are required with alternative doses of the compound used by us, or with compounds derived from other sources.

Antirheumatic Agents↗
PubMed1999

Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly different from the Tortuga formulation and that all three formulations exhibited absorption rate-limited elimination.

Adult↗
PubMed1998

Thalidomide: new preparation. For well-defined indications.

(1) Thalidomide is highly teratogenic. It can also cause irreversible neuropathy. (2) In type II lepra reactions evidence of efficacy at a dose of 400 mg/day is based on a few relatively old comparative trials and above all a review of more than 4,500 cases. Most patients feel a benefit within 24-48 hours after beginning the treatment, but most also require lengthy treatment at a reduced dose (25-100 mg/day) to avoid relapses. (3) Two placebo-controlled trials involving a total of 130 patients have shown the efficacy of thalidomide in the treatment of severe recurrent aphthous disease. (4) In Jessner-Kanoff disease, a mild condition, the efficacy of thalidomide has been shown in a single placebo-controlled trial. (5) In chronic lupus erythematosus, non comparative trials have shown remission from skin lesions in patients resistant to previous treatments. (6) In the curative treatment of chronic graft-versus-host disease in bone marrow graft recipients, thalidomide has been assessed only in non comparative trials involving a few dozens of patients.

Behcet Syndrome↗
PubMed2000

Thalidomide in multiple myeloma.

Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value in the disease. Based on the increased angiogenesis observed in myeloma, thalidomide (Thalomid) has been studied as antiangiogenic therapy. Although its mechanism of action in myeloma is unclear, several trials show that thalidomide is active in 25% to 35% of patients with relapsed myeloma. Since many patients who respond have failed other active regimens, including transplantation, these results are impressive. Major toxicities include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine its role as initial treatment for myeloma. Trials are also underway combining thalidomide with other active agents. This article summarizes the current status of thalidomide therapy in myeloma.

Angiogenesis Inhibitors↗
PubMed2001

Salvage therapy with thalidomide in multiple myeloma patients relapsing after autologous peripheral blood stem cell transplantation.

BACKGROUND AND OBJECTIVES: The introduction of high-dose therapy with stem cell support has significantly improved the outcome of patients with multiple myeloma (MM) in terms of increased complete remission (CR) rate and extended survival, both disease-free and overall. Few options, however, are presently available for patients who relapse after single or double autologous stem cell transplantation (SCT). Thalidomide, a glutamic acid derivative with anti-angiogenetic properties, has been recently proposed as salvage treatment for such patients. The present study was aimed at evaluating thalidomide as single agent therapy for patients who had previously received autologous peripheral blood stem cell transplantation. DESIGN AND METHODS: From October 1999 to August 2000, 11 patients (7 males/4 females) who had relapsed after single (n = 4) or double (n = 7) autologous peripheral blood SCT were enrolled in the trial. Thalidomide, always employed as a single agent, was initially administered at a dose of 100 mg/day; if well tolerated, the dose was increased serially by 200 mg every other week to a maximum of 800 mg/day. RESULTS: The median administered dose was 600 mg/day. WHO grade > II toxic effects were constipation, lethargy, and leukopenia. Four patients (36%) showed > 50% reduction in serum M protein concentration and 4 showed > 25% reduction, for a total response rate averaging 72%. After a median follow-up of 5 months, 3 out of 8 responding patients are alive and progression-free and 5 patients have relapsed. INTERPRETATION AND CONCLUSIONS; These data confirm that thalidomide is active in poor-prognosis MM patients such as those relapsing after autologous SCT, and could thus deserve further testing in combination therapy.

Adult↗
PubMed2001

[Role of thalidomide in the treatment of multiple myeloma].

Multiple myeloma is a relatively common hematologic malignancy with no definitive treatment available. Although, therapy may include allogenic bone marrow transplantation, high-dose ablative chemotherapy followed by bone marrow or peripheral stem cell transplantation, melphalan/corticosteroid therapy, alpha-interferon treatment, and combined cytostatic chemotherapy, currently none of these alternatives offers cure for the disease. Thalidomide is an infamous molecule for its teratogenicity, yet it possesses potent immunomodulatory, anti-angiogeneic and, in higher concentrations, direct anti-myeloma-cell properties. At present, the drug is only approved for the treatment of erythema nodosum of leprosy, however, there are several preliminary results that show clinical efficacy in multiple myeloma. This drug has especially potent anti-myeloma effects in combinations with dexamethasone and certain cytostatic chemotherapeutic agents. The effects are evident both in polyresistant, and relapsing myeloma, a form with no accepted effective treatment options. In this paper, the fundamental molecular and cellular effects of thalidomide are summarized then the most important clinical studies with thalidomide are reviewed. It is the authors' hope that thalidomide will soon be a full member of the medical arsenal in the fight against multiple myeloma.

Antineoplastic Agents↗