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PubMed2002

Thalidomide as salvage therapy for VAD-refractory multiple myeloma prior to autologous PBSCT.

Several trials have shown the activity of thalidomide (THAL) in relapsed multiple myeloma (MM) patients failing PBSCT or conventional chemotherapy. PBSCT is considered standard treatment for most patients requiring therapy for MM; however, patients with VAD-resistant disease may not be able to receive PBSCT due to rapidly advancing disease. We report four cases of VAD-refractory MM salvaged with THAL + VAD followed by PBSCT. All patients underwent stem cell mobilization with cyclophosphamide (Cy) (4.5 g/m(2)) and GMCSF. Melphalan (140-200 mg/m(2)) was given as conditioning. All patients engrafted within 12-16 days after PBSCT. Day +100 evaluation showed the following: very good partial response (n = 1) and complete response (n = 3). After a median follow-up to 153 days, two patients continue to take THAL with no signs of disease progression. One patient developed CHF and was taken off THAL while another patient has died of progressive disease while on THAL (MTD 50 mg). In conclusion, VAD-refractory patients were salvaged with the addition of THAL to VAD. They were subsequently able to undergo autologous PBSCT for MM, which will likely improve their overall survival. This suggests that THAL and other related immunomodulatory drugs may prove useful for initial MM therapy in combination with standard chemotherapy followed by PBSCT.

Aged↗
PubMed2004

Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma.

PURPOSE: The efficacy of low-dose thalidomide (THAL) plus dexamethasone (DEX) has been evaluated in myeloma. The clinical outcome of patients treated with THAL-DEX was compared with that of a control group treated with conventional chemotherapy (CC). EXPERIMENTAL DESIGN: A total of 120 relapsed/refractory patients to one (52%), or two or more(48%) lines of chemotherapy were treated with THAL 100mg/day (continuous) and DEX 40 mg (days 1-4 of each month). Their clinical outcome was compared to a control group of 120 patients frequency matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. Clinical characteristics were homogeneous in the two groups. RESULTS: In patients treated after one line of chemotherapy, THAL-DEX significantly improved outcome. Median progression-free survival (PFS) was superior in THAL-DEX group versus CC group (17 months versus 11 months, P = 0.0024). The median survival for THAL-DEX patients has not to been reached, but the probabilities of survival at 3 years were 60% after THAL-DEX and 26% after CC (P = 0.0016). The clinical outcome of patients receiving THAL-DEX or CC after two or more lines of chemotherapy, was similar. In the THAL-DEX group, the medianPFS was 11 months compared to 9 months in the CC group (P = NS). No differences in overall survival (OS) were observed (median OS 19 months for both THAL-DEX and CC). CONCLUSIONS: As first salvage regimen, THAL-DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL-DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit.

Dexamethasone↗
PubMed2004

Enantioselective synthetic thalidomide receptors based upon DNA binding motifs.

A series of molecularly imprinted polymer (MIP) synthetic receptors selective for the sedative thalidomide (5) have been designed and synthesized based upon the functional monomer 9-(2'-methacryloyloxyethyl)adenine (2). (1)H-NMR studies were used to establish the existence of DNA-like binding interactions between 2 and the template (5). A series of ethylene glycol dimethacrylate cross-linked copolymers was synthesized using either 2 or methacrylic acid, or a combination of these functional monomers. Zonal HPLC studies demonstrated enantioselectivity (alpha = 2.11) and ligand selectivity which could be attributed to the interaction of 2 with the imide moiety of 5. Compound 2 provided a more significant contribution to the binding of 5 than methacrylic acid, though a combination of these two functional monomers resulted in improved enantioselectivity. Frontal chromatographic and batch binding studies confirmed the observed differences in affinity of the imprinted and reference polymers for the template.

Adenine↗
PubMed2001

Thalidomide in agnogenic and secondary myelofibrosis.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder involving disregulation of angiogenesis and immunomodulatory mechanisms. Thalidomide (Thal) retains antiangiogenic, immunomodulatory and cytokine regulatory properties and recently it has been used successfully in multiple myeloma. Here, we report our experience in 10 MMM patients treated with Thal. Patients with agnogenic MMM treated in an early phase of the disease obtained significant benefits from the therapy and remain transfusion-free. In contrast, all secondary MMM failed to respond. These preliminary findings confirm that Thal plays a role in MMM therapy, although the efficacy in the different phases of the disease must be further evaluated.

Adult↗
PubMed2001

Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion.

Thalidomide (Thal) is a drug with anti-angiogenic properties. To explore whether the effect of Thal on angiogenesis is associated with a reduction of angiogenic cytokine levels in progressive multiple myeloma (MM), plasma levels of basic fibroblast growth factor, vascular endothelial growth factor, interleukin 6, tumour necrosis factor-alpha and hepatocyte growth factor (HGF) were measured in 51 patients at 0, 3 and 6 months of Thal therapy. After 6 months of treatment, 26 patients were considered to be responsive to Thal therapy, including 17 minimal responses, eight partial responses and one complete response. Only HGF (decreasing, P = 0.02) in the group of responsive patients showed a statistically significant change over a period of 6 months. Because HGF levels are known to correlate to MM tumour burden, we conclude that the mechanism of action of Thal in MM is not caused by a specific inhibition of angiogenic cytokine secretion.

Adult↗
PubMed2003

Plasma levels of tumour necrosis factor alpha and interleukin-6 predict progression-free survival following thalidomide therapy in patients with previously untreated multiple myeloma.

We studied marrow angiogenesis and plasma levels of angiogenic cytokines in 38 patients receiving thalidomide therapy for previously untreated myeloma. The effect of therapy and the relationship of cytokine levels to myeloma cell proliferation, bone marrow microvessel density and progression-free survival (PFS) were studied. High pretreatment tumour necrosis factor-alpha (TNFalpha) levels (> 11 pg/ml) and increased interleukin (IL)-6 of > 2 pg/ml predicted for poorer PFS (TNFalpha, 48% versus 74% at 2 years, P = 0.01; IL-6, 24% versus 70% at 2 years, P = 0.01). None of the other parameters predicted response or PFS, and no significant changes in cytokine levels occurred with therapy.

Adult↗
PubMed1997

Thalidomide therapy of established collagen-induced arthritis (CIA) not accompanied by an evident Th2 shift.

Thalidomide, a drug likely to affect the cytokine pattern, was administered orally to mice at various stages of CIA. Treatment (150 mg/kg per day by gavage, 5 days/week), started 6 weeks post-immunization, i.e. at the height of the disease, significantly reduced arthritis, and appeared also to reduce the level of inflammation as judged by neutrophil chemiluminescence. With treatment started 9 weeks post-immunization the effect on arthritis was no longer statistically significant, and when started at 14 weeks was lost. Over a dose range of up to 150 mg/kg per day the treatment had no effect on either interferon-gamma (IFN-gamma) or IL-4 mRNA levels. The treatment is therefore not likely to have operated via a shift in the Th1/Th2 balance.

Animals↗
PubMed2000

The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha (TNF-alpha) expression in acutely and chronically infected cells in vitro.

We investigated the in vitro effect of the water-soluble, highly stable thalidomide analogue CC-3052 on HIV-1 expression and TNF-alpha production in latently infected promonocytic U1 cells, acutely infected T cells and monocyte-derived human macrophages (MDM), and in mitogen-stimulated ex vivo cultures from patients with primary acute HIV-1 infection. HIV-1 expression was assessed by Northern blot analysis of RNAs, and ELISA for p24 antigen release and reverse transcriptase (RT) activity. TNF-alpha expression was evaluated by RT-polymerase chain reaction (PCR)-ELISA for mRNA and ELISA for protein secretion. We demonstrated that CC-3052 is able to inhibit HIV-1 expression, as evaluated by mRNA, p24 release and RT activity, in phorbol myristate acetate (PMA)- and cytokine-stimulated U1 cells. Furthermore, CC-3052 inhibited HIV-1 expression, as evaluated by p24 and RT activity, in acutely infected MDM and T cells. As far as TNF-alpha is concerned, CC-3052 significantly reduced TNF-alpha mRNA and protein secretion in PMA-stimulated U937 and U1 cells, and in PMA-stimulated uninfected and acutely infected MDM. Consistently, the addition of CC-3052 reduced TNF-alpha production in phytohaemagglutinin (PHA) and lipopolysaccharide (LPS)-stimulated whole blood cultures from patients during the primary acute phase of HIV-1 infection. Since TNF-alpha is among the most potent enhancers of HIV-1 expression, the effect of CC-3052 on TNF-alpha may account for its inhibitory activity on HIV-1 expression. Given the well documented immunopathological role of TNF-alpha and its correlation with viral load, advanced disease and poor prognosis, CC-3052 could be an interesting drug for the design of therapeutic strategies in association with anti-retroviral agents.

Anti-HIV Agents↗
PubMed2002

Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells.

Thalidomide (Thd) is clinically useful in a number of conditions where its efficacy is probably related to its anti-TNF-alpha activity. More recently, Thd has also been shown to co-stimulate T cells and second generation co-stimulatory (IMiD trade mark ) analogues are currently being assessed in the treatment of cancer patients. However, in contrast to their known suppressive effects during inflammatory stimuli, the effects of Thd/IMiDs on TNF-alpha and TNF receptors (TNFRs) during T cell co-stimulation are not known. We sought to determine the effect of Thd, two clinically relevant IMiDs (CC-4047, ACTIMID trade mark and CC-5013, REVIMID trade mark ) and a non-stimulatory SelCID analogue (CC-3052) on TNF-alpha production and on the expression and shedding of TNFRs during co-stimulation. We found that co-stimulation of PBMC with Thd/IMiDs, but not CC-3052, prevented alphaCD3-induced T cell surface expression of TNFR2 and thereby reduced soluble TNFR2 (sTNFR2) levels. However, there was no effect on total (surface/intracellular) TNFR2 protein expression, suggesting inhibition of trafficking to the cell membrane. The extent of co-stimulation by Thd/IMiDs (assessed by CD69/CD25 expression and IL-2/sIL-2Ralpha production) was similar for CD4+ and CD8+ T lymphocytes and correlated with TNFR2 inhibition. Co-stimulation, but not the early inhibitory effect on TNFR2, was IL-2-dependent and led to increased TNF-alpha production by both CD4+ and CD8+ T lymphocytes. The clinical relevance of this observation was confirmed by the elevation of serum TNF-alpha during REVIMID trade mark treatment of patients with advanced cancer. Together, these results suggest a possible role for TNF-mediated events during co-stimulation and contrast with the TNF inhibitory effects of Thd and its analogues during inflammatory stimuli.

Adjuvants, Immunologic↗
PubMedDate not supplied

Successful thalidomide treatment of severe infantile Behçet disease.

We describe an 11-month-old child with giant ulcers of the buccal mucosa, necrosis of the tongue, abdominal tenderness, and severe diarrhea due to Behçet disease. Treatment with thalidomide resulted in prompt recovery of the mucocutaneous lesions and gastrointestinal manifestations.

Behcet Syndrome↗
PubMed2003

Treatment of Waldenstrom's macroglobulinemia with clarithromycin, low-dose thalidomide, and dexamethasone.

Twelve patients with Waldenstrom's macroglobulinemia (WM) underwent treatment with the nonmyelosuppressive combination regimen BLT-D: clarithomycin (Biaxin [BXN], Abbott Laboratories, Abbott Park, IL) 500 mg orally twice daily, low-dose thalidomide (THAL) 50 mg orally escalated to 200 mg daily, and dexamethasone (DXM) 40 mg orally once weekly all with modification for toxicity. Omeprazole (correction of omepraxole) 20 mgm orally twice daily for 2 days with the DXM, and enteric-coated aspirin 81 mg orally daily were also administered. Twelve patients have been evaluated. All had previously received at least one purine analogue or alkylating agent. Five had a reduction in either leukocytes and/or platelets prior to treatment, of which three were disease-related. Median age was 62 years. All patients received a minimum of 6 weeks of therapy. Of the 12 patients, 10 had a significant response (83%) consisting of three near complete, three major, four partial, and two minor responses. Four of five had restoration of reduced blood counts. Two with minor responses did not receive sufficient dose escalation due to toxicity. Median time on therapy was 7 months (range, 3 to 28 months). Patients were removed from therapy primarily due to neurotoxicity. Drug resistance occurred in three patients, with one transformation to large cell lymphoma. Toxicity was as follows: gastrointestinal (primarily constipation), 42%; neurological, 100%; endocrine, 42%, and thrombotic, 8%. Most toxicities were World Health Organization (WHO) grade 1 or 2; however, neurological toxicity was more prominent and severe in WM patients than in myeloma. BLT-D is effective in WM. Because of its toxicity, predominantly neurological, BLT-D may best serve as an induction regimen or to "rescue" patients with refractory disease or disease-related low counts.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

[Presacral meningocele in thalidomide-induced embryopathy].

A now 27-year-old man, known to have a thalidomide embryopathy with multiple malformations, including a sacral deformity, developed in the course of a few weeks a disorder of bladder emptying, colicky lower abdominal pain and, finally, abnormal stools. Exploratory laparotomy revealed an anterior sacral meningocele, confirmed by computed tomography with intrathecal contrast medium injection. After surgical removal of the meningocele all bladder and rectal disorders disappeared. The course of the disease and the radiological findings are typical of a space-occupying anterior sacral meningocele.

Abnormalities, Drug-Induced↗
PubMed2002

Thalidomide therapy for cicatricial pemphigoid.

Cicatricial pemphigoid is a chronic, presumed autoimmune, blistering disease of the mucous membranes and occasionally of the skin. The characteristic feature is scarring at the sites of healing. We report the use of thalidomide as a therapeutic agent to control previously resistant disease.

Aged↗
PubMed2002

Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis.

Systemic onset juvenile rheumatoid arthritis unresponsive to nonsteroidal anti-inflammatory drugs may be controlled with corticosteroids, but these drugs have significant side effects. We report 2 steroid-dependent children with systemic onset juvenile rheumatoid arthritis who did not respond to multiple nonsteroidal anti-inflammatory drugs, methotrexate, azathioprine, cyclosporine, and etanercept. Both children had significant improvement with thalidomide therapy.

Adolescent↗
PubMed1990

Drug therapy in pregnancy: the lessons of diethylstilbestrol, thalidomide, and bendectin.

A pregnant woman and the fetus she carries face health risks from many sources. One risk that requires ongoing vigilance is the use of prescription drugs during pregnancy. The international health care community has been sensitized to the risks of drug use during pregnancy because of three pharmaceuticals that have caused widespread crises for mothers and their offspring. The crises that diethylstilbestrol, thalidomide, and, to a lesser extent, Bendectin have created in the past four decades are reviewed in this article. The lessons these drug crises can teach us are articulated in the belief that similar crises may be averted in the future.

Abnormalities, Drug-Induced↗
PubMed2006

A phase II study of thalidomide and vinblastine for palliative patients with Hodgkin's lymphoma.

INTRODUCTION: Patients with Hodgkin's Lymphoma (HL) who relapse or progress after primary therapy and subsequent high dose chemotherapy with autologous stem cell transplantation (ASCT) cannot be cured with conventional treatment. We combined thalidomide (THAL), an agent with anti-angiogenic and immunomodulatory properties, with vinblastine, which is active after ASCT, to determine the objective response rate, improvement in B symptoms and toxicity in patients with refractory HD. METHODS: Patients were eligible if they HD that progressed after chemotherapy and ASCT or had declined or were ineligible for curative therapy. Treatment consisted of THAL 200 mg orally given daily. After 2 weeks, VBL 6 mg IV was given weekly x 6 doses on an eight-week cycle. Response and toxicity assessment occurred following each cycle. RESULTS: Eleven patients were enrolled, 1 progressed within 6 days of study enrollment and was subsequently treated with alternative palliative therapy and thus 11 patients are response evaluable and 10 are evaluable for toxicity. PATIENT CHARACTERISTICS: relapsed after ASCT: 7; median number of prior chemotherapy regimens: 3 (range 1-5); median time to progression post-ASCT: 7 months (range 2-29). Four patients had a partial response to treatment (response rate 36%); two patients had stable disease. B symptoms were present at enrollment in four patients and resolved completely on treatment in two patients. Five had disease progression within 3 months of starting treatment. The median duration of response was 9 months (range 0-22 months). Toxicity was mild and limited to grade 2 neuropathy in 6 patients and grade 2 or 3 neutropenia in 4 patients. CONCLUSIONS: In this small study in chemotherapy- refractory HL, THAL and VBL demonstrated encouraging activity with some durable responses and acceptable toxicity. These results suggest that chronic low dose chemotherapy combined with less toxic immunomodulatory or anti-angiogenic drugs warrants further study.

Administration, Oral↗
PubMed2003

Advances in the treatment of multiple myeloma: the role of thalidomide.

Multiple myeloma (MM) accounts for 1% of all malignancies and 10% of malignant hematological neoplasms. In spite of high-dose therapy with stem cell rescue, relapse and disease resistance are common events in the course of the disease. Thalidomide (Thal) has been successfully used in such situations and it's use has also been expanded to the up-front therapy and as adjuvant to stem cell transplantation. Here, we review the underlying concepts and current clinical data regarding Thal in the treatment of MM.

Antineoplastic Combined Chemotherapy Protocols↗