Original Article
Thalidomide for the Treatment of Chronic Graft-versus-Host Disease
N Engl J Med 1992; 326:1055-1058April 16, 1992
- Abstract
- Abstract
Background
Allogeneic bone marrow transplantation is an accepted therapy for hematologic cancer, aplastic anemia, and inherited immunodeficiencies. Chronic graft-versus-host disease (GVHD) is the principal complication in patients surviving more than 100 days. Thalidomide has been shown experimentally to be effective in treating GVHD.
Methods
We treated 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with "high-risk" chronic GVHD (identified as having at least two of the following three risk factors: chronic GVHD that has evolved from acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction; such patients have a high mortality rate) with thalidomide in a dose that produced a plasma level of 5 μg per milliliter two hours after administration. Therapy was continued for three months after a complete response or for six months after a partial response.
Results
The overall actuarial survival of all enrolled patients was 64 percent. Survival was 76 percent among the patients receiving salvage therapy for refractory GVHD and 48 percent among those with high-risk GVHD. A complete response was observed in 14 patients, a partial response in 12 patients, and no response in 18. Side effects were minor, most notably sedation in almost all patients. In this preliminary trial, thalidomide appeared to be safe and effective for the treatment of chronic GVHD. A trial comparing thalidomide with prednisone in patients with newly diagnosed chronic GVHD will be required to demonstrate its relative efficacy. (N Engl J Med 1992;326:1055–8.)
Conclusions
Media in This Article
Figure 1
Actuarial Survival of 44 Patients with Refractory or High-Risk Chronic GVHD Treated with Thalidomide.Table 1
Characteristics at Entry of 44 Patients with Chronic GVHD.Article Activity
- Article
CHRONIC graft-versus-host disease (GVHD) is the main late complication of allogeneic bone marrow transplantation, occurring in approximately 40 percent of patients who survive for 100 days after transplantation. If extensive chronic GVHD is not treated, less than 20 percent of patients recover completely.1 Although mortality of only 27 percent has been reported for chronic GVHD, a recent review found that 52 percent of all patients with that diagnosis died, the majority of infection.2 , 3 Three features of chronic GVHD at presentation appeared to be predictive of death: progressive disease (chronic GVHD evolving from active acute GVHD), lichenoid skin or mucous-membrane changes, and hepatic dysfunction. Patients with no such risk factors had an actuarial survival of 70 percent at six years, whereas patients with two or more of these risk factors had a projected survival of 20 percent. The latter group has been designated as having "high-risk" chronic GVHD.
We have been studying the use of thalidomide to treat chronic GVHD. This drug was initially used as a sedative, but it was later found to have immunosuppressive properties.4 Because of its teratogenic effects and consequent limited availability, its immunosuppressive effects have been incompletely explored. Several small clinical trials of thalidomide for refractory autoimmune disorders suggested that it was a potent immunosuppressive agent.5 Moreover, it was found to be effective in the treatment of chronic GVHD in a rat model of the disease.6 We present a preliminary report of the use of thalidomide to treat patients with high-risk chronic GVHD and patients with refractory GVHD, who had no response to at least one course of standard therapy for this disorder.
Methods
Forty-four patients with either high-risk chronic GVHD or refractory GVHD were enrolled in this trial; patients who were unable to take oral medications or who had peripheral neuropathy were not eligible. The clinical characteristics of the 44 patients are shown in Table 1Table 1
Characteristics at Entry of 44 Patients with Chronic GVHD.. The preparative regimens for transplantation have been reported elsewhere7; they included cyclophosphamide (200 mg per kilogram of body weight given over a four-day period) plus either busulfan (16 mg per kilogram) or total-body irradiation (12 Gy [ 1200 rad], with shielding of the lungs on the third day), or busulfan (16 mg per kilogram over a four-day period), etoposide (30 mg per kilogram over a three-day period), and cyclophosphamide (150 mg per kilogram over a three-day period).7 Forty patients received bone marrow from an HLA-identical sibling, whereas four patients received mismatched marrow from either siblings or parents. Two patients had undergone transplantation more than once, with the development of GVHD after the last transplantation. The majority of the patients received cyclosporine as prophylaxis against acute GVHD. Three patients received marrow that had been depleted of lymphocytes as previously reported.8 The diagnosis of chronic GVHD was based on the appearance of its clinical features, but in all cases the diagnosis was confirmed histologically according to standard criteria.9 Subclinical chronic GVHD (i.e., evidence of GVHD on biopsy, without evidence on clinical examination) was not treated. All patients met the criteria for entry and signed informed-consent forms approved by the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions.
In the first four patients who entered the study, all other immunosuppressive medications were discontinued at the start of treatment with thalidomide (Champion Farmaceutica, São Paulo, Brazil). In patients with refractory chronic GVHD who were enrolled thereafter, current medications for GVHD were maintained for three months after the start of thalidomide treatment, to allow the dose of the drug to be adjusted. In patients with high-risk chronic GVHD, prophylactic treatment for acute GVHD — i.e., cyclosporine — was maintained for six months after transplantation and then discontinued; in two of these patients, immunosuppressive agents were discontinued when chronic GVHD developed, and thalidomide alone was begun.
The initial dose of thalidomide was 200 mg given four times a day in adults and 3 mg per kilogram of body weight given four times a day in children. The plasma level of thalidomide was measured by high-performance liquid chromatography performed according to published techniques10; it was monitored two hours after a dose and maintained at a minimum of 5 μg per milliliter. Seven adult patients required larger dosages (1200 to 1600 mg per day) to maintain this level. Patients also received trimethoprim–sulfamethoxazole tablets twice a day as prophylaxis against Pneumocystis carinii infection. Those unable to tolerate this medication were given penicillin daily (250 mg twice a day) and aerosolized pentamidine monthly. The median duration of thalidomide therapy (as of May 1, 1991) was 240 days (range, 2 to 700).
Patients were reevaluated every three months, and a skin or oral biopsy was performed to assess their response when changes in therapy were considered. Patients were judged to have had no response if their chronic GVHD worsened, if they had no improvement after six months, or if they died of any cause before their first evaluation at three months. Patients were classified as having had a partial response if they had improvement of more than 50 percent but less than 100 percent in all affected organ systems (i.e., as indicated by a decrease in the serum bilirubin level, the distribution of lichenoid skin changes, or the distribution of active sclerodermatous skin changes; the return of dermal appendages [hair]; a decrease in the distribution of oral lesions; or resolution of ulceration in cases of persistent lichenoid oral changes or erythema). Patients were considered to have had a complete response if active chronic GVHD resolved completely in all organ systems; their treatment was continued for three additional months, and their dose of medication was then tapered (i.e., reduced by 25 percent every two weeks). Patients with a partial response were treated for an additional six months after their maximal response was achieved.
Results are presented as of May 1, 1991. Survival was measured from the initiation of thalidomide treatment, and survival rates were estimated according to the Kaplan–Meier method.
Results
When they entered the study, the 23 patients receiving second-line therapy for refractory chronic GVHD (i.e., those in whom at least one other treatment had failed) had a median serum bilirubin concentration of, 42.5 μmol per liter (range, 3.4 to 445), a median white-cell count of 8.2×109 per liter (8200 per microliter) (range, 1.8 to 14×109 per liter [1800 to 14,000 per microliter]), a median platelet count of 262×109 per liter (262,000 per microliter) (range, 14 to 609×109 per liter [14,000 to 609,000 per microliter]), and a median interval of 616 days between transplantation and the initiation of thalidomide therapy (range, 175 to 2414).
The 21 patients with high-risk chronic GVHD were treated immediately (i.e., those who had two of the following three characteristics at the time of diagnosis of chronic GVHD: chronic GVHD evolving from active acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction). At entry, these patients had a median bilirubin concentration of 71.4 μmol per liter (range, 3.4 to 476). Their median white-cell count was 3.4×109 per liter (3400 per microliter) (range, 0.4 to 8×109 per liter [400 to 8000 per microliter]); seven patients had counts of less than 2×109 per liter (2000 per microliter). The median platelet count of the 21 patients was 90×109 per liter (90,000 per microliter) (range, 2 to 378×109 per liter [2000 to 378,000 per microliter]); 15 patients had counts of less than lOO×lO9 per liter (100,000 per microliter). Eleven of the 21 patients were dependent on platelet transfusions. All but 2 of the 21 patients had chronic GVHD of progressive onset, and all except these 2 patients were receiving cyclosporine and prednisone when chronic GVHD developed. At entry, 11 patients had two of the three factors characterizing high-risk GVHD, and 10 had all three factors. The median interval between transplantation and entry into the study was 125 days (range, 29 to 379).
Treatment with thalidomide was started in the 23 patients with refractory disease when their previous regimen for chronic GVHD was judged to have failed. Their previous regimens and the lengths of treatment are shown in Table 2Table 2
Previous Regimens of 23 Patients with Refractory Chronic GVHD.; together, these patients had previously received 33 courses of therapy.Two patients did not comply with their regimen of medication and were withdrawn from the study. Of the 21 patients with high-risk chronic GVHD, 6 were unable to absorb oral medications, as shown by their plasma thalidomide levels (4 had severe diarrhea and 2 had refractory nausea and vomiting); these 6 patients were included among the patients judged to have no response.
Survival and Response
Overall actuarial survival was 64 percent; survival according to treatment group was 76 percent among the patients with refractory chronic GVHD and 48 percent among those with high-risk chronic GVHD (Table 3Table 3
Survival and Response to Thalidomide Treatment. and Fig. 1Figure 1Actuarial Survival of 44 Patients with Refractory or High-Risk Chronic GVHD Treated with Thalidomide.). A complete response to treatment was achieved in 7 of the 21 patients receiving thalidomide as primary therapy and 7 of the 23 patients receiving thalidomide as salvage therapy. A partial response occurred in 1 patient treated for high-risk chronic GVHD and 11 patients treated for refractory GVHD.Response rates are shown according to previous regimen in Table 2. Eight patients underwent more than one regimen before receiving thalidomide. Eighteen patients were considered to have had no response to thalidomide, of whom 13 had high-risk GVHD and 5 had refractory GVHD. Nine patients (three with high-risk disease and six with refractory disease) are still receiving treatment for chronic GVHD. One patient had a recurrence of chronic GVHD after he stopped taking thalidomide; he responded to the reinstitution of therapy.
Mortality
Sixteen patients enrolled in the trial have died. The primary cause of death was chronic GVHD, with five patients dying of organ failure and three others dying of fungal infection with progressive chronic GVHD. Two patients died of bacterial infection. Two patients died of interstitial pneumonitis due to cytomegalovirus, and another died of idiopathic interstitial pneumonitis. One patient each died of P. carinii pneumonia, pulmonary embolism, and relapse of leukemia.
Toxicity
Sedation was observed in virtually all patients; 91 percent reported sleepiness, especially during the first few weeks of therapy. Twenty-two patients (50 percent) had at least a single episode of constipation. Four patients had numbness and tingling of the hands or the feet (or both) that were consistent with a peripheral neuropathy; their medication was discontinued, and their symptoms resolved over the following days or weeks. The only patient among these four who was able to return for neurologic evaluation at the time of his symptoms was found to have progressive chronic GVHD and was considered not to have responded to treatment. His neurologic symptoms were due to nerve entrapment.
Infection
Infections were diagnosed in 19 patients (Table 4Table 4
Infectious Complications of Thalidomide Treatment.), 9 of whom died. Serious fungal infections, primarily infections with aspergillus, occurred in six patients, two of whom had fungal infections when thalidomide therapy began. Other infections included sinusitis, cellulitis, and meningitis. Bacteremia, especially in the patients with high-risk chronic GVHD, was judged to be due to infection of intravenous catheters. Interstitial pneumonitis occurred in four patients; it was caused by cytomegalovirus in two and by P. carinii in one.Discussion
Chronic GVHD remains the most important long-term complication of allogeneic bone marrow transplantation. As more patients receive allogeneic transplants and as older patients are considered for transplantation, chronic GVHD is increasing in importance.
A series of reports1 , 11 , 12 on the natural history and treatment of chronic GVHD have emphasized the need for immunosuppressive therapy. Less than 20 percent of untreated patients recover completely.1 A randomized trial in which prednisone plus placebo was compared with prednisone plus azathioprine showed that the group of patients given the latter combination had more infections and worse survival than the prednisone—placebo group (actuarial survival at five years, 47 percent vs. 61 percent).11 The combination of prednisone and cyclosporine improved survival in patients with thrombocytopenia (platelet count, <100×109 per liter [< 100,000 per microliter]) or treatment failure, from 26 percent to 51 percent.12 At present, patients without thrombocytopenia receive either prednisone or cyclosporine with prednisone.13
We became interested in thalidomide because of its purported immunosuppressive properties, confirmed in animal models of acute and chronic GVHD.6 , 14 15 16 A plasma thalidomide level of 5 μg per milliliter was necessary to produce a maximal response. The results obtained in animals were sufficiently encouraging to introduce the drug into the clinic.
The patients included in our trial were similar to those studied by Sullivan et al., who were treated with cyclosporine and prednisone.12 In both trials, the response rate and the survival rate were remarkably similar. Other investigators have also observed responses in patients given thalidomide for GVHD.17 18 19 20 21
Four of our 44 patients who received thalidomide had relapses of their primary malignant disease. (One patient with pancytopenia was found to be in relapse on bone marrow biopsy performed at the start of thalidomide therapy.) This rate of relapse is consistent with that observed among patients who have received agents other than thalidomide,2 suggesting that the antitumor benefit of chronic GVHD is not lost in patients treated with thalidomide.
Our results indicate that thalidomide has acceptable levels of toxicity, with relatively mild side effects as compared with those of other regimens. Furthermore, thalidomide does appear to have immunosuppressive properties. A multiinstitutional randomized trial comparing thalidomide with standard therapy including prednisone in patients with chronic GVHD will be required to establish its relative effectiveness.
Supported in part by grants (R01-CA-44783 and CA-15396) from the National Institutes of Health. Dr. Vogelsang is a scholar of the Leukemia Society of America.
*Deceased.
Source Information
From the Bone Marrow Transplant Unit, Department of Oncology (G.B.V., A.D.H., V.A., O.M.C., J.R.W., G.W.S.), and the Departments of Dermatology (E.R.F., R.L.C., L.S.L.), Pathology (W.E.B.), and Ophthalmology (D.A.J.), Johns Hopkins University School of Medicine, Baltimore. Address reprint requests to Dr. Vogelsang at the Johns Hopkins Oncology Center, 600 N. Wolfe St., Rm. 3–127, Baltimore, MD 21205.
- References
References
1
Sullivan
Web of Science | Medline2
Wingard
Web of Science | Medline3
Storb
Web of Science | Medline4
Sheskin
Web of Science | Medline5
Barnhill
CrossRef | Web of Science | Medline6
Vogelsang
Web of Science | Medline7
Jones
Web of Science | Medline8
Wagner
Web of Science | Medline9
Shulman
Web of Science | Medline10
Chen
Web of Science | Medline11
Sullivan
Web of Science | Medline12
Sullivan
Web of Science | Medline13
Sullivan 14
Vogelsang
CrossRef | Web of Science | Medline15
Vogelsang
Web of Science16
Vogelsang
Web of Science | Medline17
McCarthy
CrossRef | Web of Science | Medline18
Saurat
CrossRef | Web of Science | Medline19
Parker 20
Boughton
Web of Science21
Heney
CrossRef | Web of Science | Medline
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1
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CrossRef2
D. Wolf, M. von Lilienfeld-Toal, A. M. Wolf, M. Schleuning, M. von Bergwelt-Baildon, S. A. E. Held, P. Brossart. (2011) Novel treatment concepts for graft versus host disease (GvHD). Blood
CrossRef3
John Harper, Paul Veys. 2011. Graft-Versus-Host Disease. , 178.1-178.12.
CrossRef4
Ming Jen Tsai, Chinpiao Chen, Sung-Ho Chen, Yen Ta Huang, Ted H. Chiu. (2011) Pomalidomide suppresses cerulein-induced acute pancreatitis in mice. Journal of Gastroenterology 46:6, 822-833
CrossRef5
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CrossRef6
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CrossRef7
Meng Chen, Sean D. Doherty, Sylvia Hsu. (2010) Innovative Uses of Thalidomide. Dermatologic Clinics 28:3, 577-586
CrossRef8
Imran Ali, Vinod K. Gupta, Hassan Y. Aboul-Enein. (2010) Supramolecular dynamics of thalidomide and its derivatives in water-sediment system. ChiralityNA-NA
CrossRef9
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CrossRef10
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CrossRef11
Sabine Tricot, Céline Berthon, Marie-Dominique Venon, Julie Gay, Remy Dulery, Aldo M Roccaro, Teru Hideshima, Irene M Ghobrial, Thierry Facon, Xavier Leleu. (2009) Thalidomide in multiple myeloma in the elderly. Aging Health 5:1, 7-18
CrossRef12
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CrossRef13
A Bjorklund, J Aschan, M Labopin, M Remberger, O Ringden, J Winiarski, P Ljungman. (2007) Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation. Bone Marrow Transplantation 40:11, 1055-1062
CrossRef14
J Lew, JA Smith. (2007) Mucosal graft-vs-host disease. Oral Diseases 13:6, 519-529
CrossRef15
Sheeba Thomas, Tiffany Richards, Donna M. Weber. 2007. Novel Agents for Previously Untreated Multiple Myeloma. , 141-168.
CrossRef16
Christopher J. Fraser, K. Scott Baker. (2007) The management and outcome of chronic graft- versus -host disease. British Journal of Haematology 138:2, 131-145
CrossRef17
M. Rosenbach, Victoria P. Werth. (2007) Dermatologic therapeutics: thalidomide. A practical guide. Dermatologic Therapy 20:4, 175-186
CrossRef18
Kenneth L. McClain, Claudia A. Kozinetz. (2007) A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatric Blood & Cancer 48:1, 44-49
CrossRef19
Waldiceu A. Verri, Thiago M. Cunha, Carlos A. Parada, Stephen Poole, Fernando Q. Cunha, Sérgio H. Ferreira. (2006) Hypernociceptive role of cytokines and chemokines: Targets for analgesic drug development?. Pharmacology & Therapeutics 112:1, 116-138
CrossRef20
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CrossRef21
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CrossRef22
Mitchell E. Horwitz, Keith M. Sullivan. (2006) Chronic graft-versus-host disease. Blood Reviews 20:1, 15-27
CrossRef23
Andrew L. Gilman, Jonathan Serody. (2006) Diagnosis and Treatment of Chronic Graft-Versus-Host Disease. Seminars in Hematology 43:1, 70-80
CrossRef24
Marie Robin, Philippe Guardiola, Th??odore Girinsky, Gabriella Hernandez, H??l??ne Esp??rou, Patricia Ribaud, Vanderson Rocha, Federico Garnier, G??rard Soci??, Eliane Gluckman, Agn??s Devergie. (2005) Low-dose Thoracoabdominal Irradiation for the Treatment of Refractory Chronic Graft-versus-Host Disease. Transplantation 80:5, 634-642
CrossRef25
B. Rojas, R. Cuhna, P. Zafirakis, J.M. Ramirez, M. Lizan-garciı´a, T. Zhao, C.S. Foster. (2005) Cell populations and adhesion molecules expression in conjunctiva before and after bone marrow transplantation. Experimental Eye Research 81:3, 313-325
CrossRef26
D Ribatti, A Vacca. (2005) Therapeutic renaissance of thalidomide in the treatment of haematological malignancies. Leukemia 19:9, 1525-1531
CrossRef27
J.J. Wu, D.B. Huang, K.R. Pang, S. Hsu, S.K. Tyring. (2005) Thalidomide: dermatological indications, mechanisms of action and side-effects. British Journal of Dermatology 153:2, 254-273
CrossRef28
Inacio R. Faver, Samantha G. Guerra, W. P. Daniel Su, Rokea el-Azhary. (2005) Thalidomide for dermatology: a review of clinical uses and adverse effects. International Journal of Dermatology 44:1, 61-67
CrossRef29
James P. Farese, Leslie E. Fox, Carol J. Detrisac, James M. Van Gilder, Sara L. Roberts, Jamie M Baldwin. (2004) Effect of thalidomide on growth and metastasis of canine osteosarcoma cells after xenotransplantation in athymic mice. American Journal of Veterinary Research 65:5, 659-664
CrossRef30
Meghan A. Higman, Georgia B. Vogelsang. (2004) Chronic graft versus host disease. British Journal of Haematology 125:4, 435-454
CrossRef31
Hobart W. Walling, Michael D. Voigt, Mary Seabury Stone. (2004) Lichenoid graft vs. host disease following liver transplantation. Journal of Cutaneous Pathology 31:2, 179-184
CrossRef32
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CrossRef33
Liang Deng, Wanhong Ding, Richard D. Granstein. (2003) Thalidomide Inhibits Tumor Necrosis Factor-alpha Production and Antigen Presentation by Langerhans Cells. Journal of Investigative Dermatology 121:5, 1060-1065
CrossRef34
Pablo Muriel, Eduardo Fernández-Martínez, Víctor Pérez-Álvarez, Francisco Lara-Ochoa, Susana Ponce, Julio García, Mineko Shibayama, Víctor Tsutsumi. (2003) Thalidomide ameliorates carbon tetrachloride induced cirrhosis in the rat. European Journal of Gastroenterology & Hepatology 15:9, 951-957
CrossRef35
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CrossRef36
Gordon R. Macpherson, Michael Franks, Andrada Tomoaia-Cotisel, Yuichi Ando, Douglas K Price, William D. Figg. (2003) Current status of thalidomide and its role in the treatment of metastatic prostate cancer. Critical Reviews in Oncology/Hematology 46, 49-57
CrossRef37
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CrossRef38
Hendrikus G.J Krouwer, Eelco F.M Wijdicks. (2003) Neurologic complications of bone marrow transplantation. Neurologic Clinics 21:1, 319-352
CrossRef39
S.James Matthews, Christopher McCoy. (2003) Thalidomide: A review of approved and investigational uses. Clinical Therapeutics 25:2, 342-395
CrossRef40
Georgia B. Vogelsang, Linda Lee, Debra M. Bensen-Kennedy. (2003) Pathogenesis and Treatment of Graft-Versus-Host Disease After Bone Marrow Transplant. Annual Review of Medicine 54:1, 29-52
CrossRef41
Mary E.D. Flowers, Paul J. Martin. (2003) Evaluation of Thalidomide for Treatment or Prevention of Chronic Graft-versus-host Disease. Leukemia & Lymphoma 44:7, 1141-1146
CrossRef42
Steve Miller, Shalini Sharda, James Rodrigue, Paulette Mehtaa. (2002) Thalidomide in Chronic Graft-versus-Host Disease after Stem Cell Transplantation: Effects on Quality of Life. International Journal of Hematology 76:4, 365-369
CrossRef43
Vincenzo Ruocco, Guido Sacerdoti, Pietro Farro, Eleonora Ruocco, Ronni Wolf. (2002) Adverse drug reactions and graft-versus-host reaction: unapproved treatments. Clinics in Dermatology 20:6, 672-678
CrossRef44
Nina Y Wines, Alan J Cooper, Michael P Wines. (2002) Thalidomide in dermatology. Australasian Journal of Dermatology 43:4, 229-240
CrossRef45
Sylvie Bastuji-Garin, Sophie Ochonisky, Pierre Bouche, Romain K Gherardi, Corinne Duguet, Zaya Djerradine, Florence Poli, Jean Revuz, . (2002) Incidence and Risk Factors for Thalidomide Neuropathy: a Prospective Study of 135 Dermatologic Patients. Journal of Investigative Dermatology 119:5, 1020-1026
CrossRef46
Andrea Thiele, Renate Bang, Michael Gütschow, Manuela Rossol, Sebastian Loos, Kurt Eger, Gisa Tiegs, Sunna Hauschildt. (2002) Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide. European Journal of Pharmacology 453:2-3, 325-334
CrossRef47
S.R Porter, J Jorge Jr. (2002) Thalidomide: a role in oral oncology?. Oral Oncology 38:6, 527-531
CrossRef48
Pascale Halle, Catherine Paillard, Michel D'Incan, Pierre Bordigoni, Christophe Piguet, Lionel De Lumley, Jean Louis Stephan, Marc Berger, Chantal Rapatel, Francois Demeocq, Justyna Kanold. (2002) Successful Extracorporeal Photochemotherapy for Chronic Graft-Versus-Host Disease in Pediatric Patients. Journal of Hematotherapy <html_ent glyph="@amp;" ascii="&"/> Stem Cell Research 11:3, 501-512
CrossRef49
J. M. Sabate, J. Villarejo, M. Lemann, J. Bonnet, M. Allez, R. Modigliani. (2002) An open-label study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn's disease. Alimentary Pharmacology and Therapeutics 16:6, 1117-1124
CrossRef50
Paul Richardson, Teru Hideshima, Kenneth Anderson. (2002) T
HALIDOMIDE : Emerging Role in Cancer Medicine. Annual Review of Medicine 53:1, 629-657
CrossRef51
CAROLYN BARIOL, ALAN P MEAGHER, CHRISTOPHER R VICKERS, DAVID J BYRNES, PAUL D EDWARDS, MICHAEL HING, ANTONY R WETTSTEIN, ANDREW FIELD. (2002) Early studies on the safety and efficacy of thalidomide for symptomatic inflammatory bowel disease. Journal of Gastroenterology and Hepatology 17:2, 135-139
CrossRef52
F Zorat, G Pozzato. (2002) Thalidomide in myelodysplastic syndromes. Biomedicine & Pharmacotherapy 56:1, 20-30
CrossRef53
Eduardo Fern
ndez-Mart
CrossRef54
J Stebbing, C Benson, T Eisen, L Pyle, K Smalley, H Bridle, I Mak, F Sapunar, R Ahern, M E Gore. (2001) The treatment of advanced renal cell cancer with high-dose oral thalidomide. British Journal of Cancer 85:7, 953-958
CrossRef55
Jeffrey R. LaDuca, David N. Herrmann, Anthony A. Gaspari. (2001) Thalidomide therapy for cutaneous lupus erythematosus: historical and practical considerations. Dermatologic Therapy 14:2, 154-166
CrossRef56
N. Basara, M.G. Kiehl, A.A. Fauser. (2001) New therapeutic modalities in the treatment of graft-versus-host disease. Critical Reviews in Oncology/Hematology 38:2, 129-138
CrossRef57
Philip M Ginsburg, Themistocles Dassopoulos, Eli D Ehrenpreis. (2001) Thalidomide treatment for refractory Crohn's disease: a review of the history, pharmacological mechanisms and clinical literature. Annals of Medicine 33:8, 516-525
CrossRef58
Christian Meierhofer, Stefan Dunzendorfer, Christian J. Wiedermann. (2001) Theoretical Basis for the Activity of Thalidomide. BioDrugs 15:10, 681-703
CrossRef59
S. Arai, G.B. Vogelsang. (2000) Management of graft-versus-host disease. Blood Reviews 14:4, 190-204
CrossRef60
Stephen J. Oliver. (2000) The Th1/Th2 paradigm in the pathogenesis of scleroderma, and its modulation by thalidomide. Current Rheumatology Reports 2:6, 486-491
CrossRef61
Deborah A. Thomas, Hagop M. Kantarjian. (2000) Current role of thalidomide in cancer treatment. Current Opinion in Oncology 12:6, 564-573
CrossRef62
T Stephens. (2000) Mechanism of action in thalidomide teratogenesis. Biochemical Pharmacology 59:12, 1489-1499
CrossRef63
Jeffrey Margolis, Georgia Vogelsang. (2000) Chronic Graft-Versus-Host Disease. Journal of Hematotherapy <html_ent glyph="@amp;" ascii="&"/> Stem Cell Research 9:3, 339-346
CrossRef64
Monika Walchner, , Michael Meurer, , Gerd Plewig, , Gerald Messer, . (2000) Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus. International Journal of Dermatology 39:5, 383-388
CrossRef65
Gunnar Juliusson, Fredrik Celsing, Ingemar Turesson, Stig Lenhoff, Magnus Adriansson, Claes Malm. (2000) Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. British Journal of Haematology 109:1, 89-96
CrossRef66
Vlassis Kontogiannis, Richard J. Powell. (2000) Use of Thalidomide in Dermatological Indications. BioDrugs 13:4, 255-265
CrossRef67
Ronaldo A Ribeiro, Mariana L Vale, Sergio H Ferreira, Fernando Q Cunha. (2000) Analgesic effect of thalidomide on inflammatory pain. European Journal of Pharmacology 391:1-2, 97-103
CrossRef68
Anne Marie Valorie. (2000) Thalidomide. A New Beginning. Cancer Practice 8:2, 101-103
CrossRef69
Steve K. Teo, Michael R. Scheffler, Karin A. Kook, William G. Tracewell, Wayne A. Colburn, David I. Stirling, Steve D. Thomas. (2000) Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women. Biopharmaceutics & Drug Disposition 21:1, 33-40
CrossRef70
&NA;. (2000) Thalidomide: new uses for an old drug. Drugs & Therapy Perspectives 15:1, 5-8
CrossRef71
Miguel R Sanchez. (2000) Miscellaneous treatments: thalidomide, potassium iodide, levamisole, clofazimine, colchicine, and d-Penicillamine. Clinics in Dermatology 18:1, 131-145
CrossRef72
Marco Zecca, Franco Locatelli. (2000) Management of Graft-Versus-Host Disease in Paediatric Bone Marrow Transplant Recipients. Pediatric Drugs 2:1, 29-55
CrossRef73
David I Stirling. (2000) Pharmacology of thalidomide. Seminars in Hematology 37, 5-14
CrossRef74
Eric A. Vasiliauskas, Lori Y. Kam, Maria T. Abreu-Martin, Philip V. Hassard, Kostas A. Papadakis, Huiying Yang, Jerome B. Zeldis, Stephan R. Targan. (1999) An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease. Gastroenterology 117:6, 1278-1287
CrossRef75
Eli D. Ehrenpreis, Sunanda V. Kane, Lawrence B. Cohen, Russell D. Cohen, Stephen B. Hanauer. (1999) Thalidomide therapy for patients with refractory Crohn's disease: An open-label trial. Gastroenterology 117:6, 1271-1277
CrossRef76
Marilyn T. Miller, Kerstin Str
CrossRef77
Mary E.D. Flowers, Emin Kansu, Keith M. Sullivan. (1999) PATHOPHYSIOLOGY AND TREATMENT OF GRAFT-VERSUS-HOST DISEASE. Hematology/Oncology Clinics of North America 13:5, 1091-1112
CrossRef78
Faruq H. Noormohamed, Michael S. Youle, Christopher J. Higgs, Karin A. Kook, David A. Hawkins, Ariel F. Lant, Steven D. Thomas. (1999) Pharmacokinetics and Hemodynamic Effects of Single Oral Doses of Thalidomide in Asymptomatic Human Immunodeficiency Virus-Infected Subjects. AIDS Research and Human Retroviruses 15:12, 1047-1052
CrossRef79
B. de Wazières, H. Gil, N. Magy, S. Berthier, D.A. Vuitton, J.L. Dupond. (1999) Traitement de l'aphtose récurrente par thalidomide à faible dose. Étude pilote chez 17 patients. La Revue de Médecine Interne 20:7, 567-570
CrossRef80
Tom L Rowland, Simon M McHugh, John Deighton, Pamela W Ewan, Rebecca J Dearman, Ian Kimber. (1999) Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor α by thalidomide: comparisons with dexamethasone. Immunology Letters 68:2-3, 325-332
CrossRef81
Tsukasa Kotoh, Dipok Kumar Dhar, Reiko Masunaga, Hideki Tabara, Mitsuo Tachibana, Hirofumi Kubota, Hitoshi Kohno, Naofumi Nagasue. (1999) Antiangiogenic therapy of human esophageal cancers with thalidomide in nude mice. Surgery 125:5, 536-544
CrossRef82
Carol Braun Trapnell, Stephen R. Donahue, Jerry M. Collins, David A. Flockhart, David Thacker, Darrell R. Abernethy. (1998) Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone*. Clinical Pharmacology & Therapeutics 64:6, 597-602
CrossRef83
D STIRLING. (1998) Thalidomide and its impact in dermatology. Seminars in Cutaneous Medicine and Surgery 17:4, 231-242
CrossRef84
Pierre Wolkenstein, Jacques Latarjet, Jean-Claude Roujeau, Corinne Duguet, Sylvie Boudeau, Loöc Vaillant, Michel Maignan, Marie-Hélène Schuhmacher, Brigitte Milpied, Alain Pilorget, Hélène Bocquet, Christian Brun-Buisson, Jean Revuz. (1998) Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. The Lancet 352:9140, 1586-1589
CrossRef85
Zhu, Deng, Diab, Zwingenberger, Bakhiet, Link. (1998) Thalidomide Prolongs Experimental Autoimmune Neuritis in Lewis Rats. Scandinavian Journal of Immunology 48:4, 397-402
CrossRef86
S. M. McHUGH, T. L. ROWLAND. (1997) Thalidomide and derivatives: immunological investigations of tumour necrosis factor-alpha (TNF-α) inhibition suggest drugs capable of selective gene regulation. Clinical & Experimental Immunology 110:2, 151-154
CrossRef87
Hartmut Link, Hans-Jochem Kolb, Wolfram Ebell, Dieter Kurt Hossfeld, Axel Zander, Dietrich Niethammer, Hannes Wandt, Hans Grosse-Wilde, Ulrich W. Schaefer. (1997) Die Transplantation hämatopoetischer Stammzellen. Medizinische Klinik 92:8, 480-491
CrossRef88
J. Blake Marriott, Michael Westby, Angus G. Dalgleish. (1997) Therapeutic potential of TNF-α inhibitors old and new. Drug Discovery Today 2:7, 273-282
CrossRef89
Jacobson, Jeffrey M., Greenspan, John S., Spritzler, John, Ketter, Nzeera, Fahey, John L., Jackson, J. Brooks, Fox, Lawrence, Chernoff, Miriam, Wu, Albert W., MacPhail, Laurie A., Vasquez, Guillermo J., Wohl, David A., . (1997) Thalidomide for the Treatment of Oral Aphthous Ulcers in Patients with Human Immunodeficiency Virus Infection. New England Journal of Medicine 336:21, 1487-1493
Full Text90
Megan L Andrews, Ivan Robertson, David Weedon. (1997) Cutaneous manifestations of chronic graft-versus-host disease. Australasian Journal of Dermatology 38:2, 53-64
CrossRef91
Edward J. Shannon, Melvyn J. Morales, Felipe Sandoval. (1997) Immunomodulatory assays to study structure-activity relationships of thalidomide. Immunopharmacology 35:3, 203-212
CrossRef92
John P. DeVincenzo, Sandra K. Burchet. (1996) PROLONGED THALIDOMIDE THERAPY FOR HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED RECURRENT SEVERE ESOPHAGEAL AND ORAL APHTHOUS ULCERS. The Pediatric Infectious Disease Journal 15:5, 465-467
CrossRef93
C. O. Audit, K. Eger, C. Aimar. (1996) Possible involvement of an acylation mechanism in thalidomide-induced teratogenesis of the newt (Pleurodeles waltl.). Development, Growth and Differentiation 38:1, 47-57
CrossRef94
Margaret H. Burroughs, Liana Tsenova-Berkova, Karen Sokol, Joachim Ossig, Elaine Tuomanen, Gilla Kaplan. (1995) Effect of thalidomide on the inflammatory response in cerebrospinal fluid in experimental bacterial meningitis. Microbial Pathogenesis 19:4, 245-255
CrossRef95
N. Blumberg, J.M. Heal. (1995) Transfusion and the immune system: a paradigm shift in progress?. Transfusion 35:10, 879-883
CrossRef96
H.M. Lazarus, J.M. Rowe. (1995) New and experimental therapies for treating graft-versus-host disease. Blood Reviews 9:2, 117-133
CrossRef97
GEOFFREY M. FORBES, JOHN M. DAVIES, RICHARD P. HERRMANN, BRENDAN J. COLLINS. (1995) Liver disease complicating bone marrow transplantation: A clinical audit. Journal of Gastroenterology and Hepatology 10:1, 1-7
CrossRef98
Kay Uthoff, Kenton J. Zehr, Paul B. Gaudin, Pankaj Kumar, Peter W. Cho, Georgia Vogelsang, Ralph H. Hruban, William A. Baumgartner, R. Scott Stuart. (1995) Thalidomide as replacement for steroids in immunosuppression after lung transplantation. The Annals of Thoracic Surgery 59:2, 277-282
CrossRef99
Tommy Eriksson, Sven Bj
CrossRef100
Daniel J. Weisdorf. (1994) Management of graft-versus-host disease. Transfusion Science 15:3, 231-242
CrossRef101
H.Joachim Deeg. (1994) Graft-versus-host disease and the development of late complications. Transfusion Science 15:3, 243-254
CrossRef102
Armitage, James O.. (1994) Bone Marrow Transplantation. New England Journal of Medicine 330:12, 827-838
Full Text103
Christopher W. Seidler, Letha E. Mills, Mary E. D. Flowers, Keith M. Sullivan. (1994) Spontaneous factor VIII inhibitor occurring in association with chronic graft-versus-host disease. American Journal of Hematology 45:3, 240-243
CrossRef104
Ana Cristina Nogueira, Reinhard Neubert, Hans Helge, Diether Neubert. (1994) Thalidomide and the immune system 3. simultaneous up- and down-regulation of different integrin receptors on human white blood cells. Life Sciences 55:2, 77-92
CrossRef105
A.M. Miller, D.W. van Bekkum, S.M. Kobb, M.B. McCrohan, S. Knaan-Shanzer. (1993) Dietary fish oil supplementation alters LTB4:LTB5 ratios but does not affect the expression of acute graft versus host disease in mice. Prostaglandins, Leukotrienes and Essential Fatty Acids 49:2, 561-568
CrossRef106
Robert Rothchild, Kerry Sanders, Kunisi S. Venkatasubban. (1993) NMR Studies of Drugs. Use of Lanthanide Shift Reagents in Polar Solvent with Thalidomide. Spectroscopy Letters 26:4, 597-619
CrossRef107
(1992) Thalidomide Neuropathy. New England Journal of Medicine 327:10, 735-735
Full Text108
Reinhard Neubert, Ana Cristina Nogueira, Diether Neubert. (1992) Thalidomide and the immune system 2. Changes in receptors on blood cells of a healthy volunteer. Life Sciences 51:26, 2107-2116
CrossRef109
Nelson J Chao. (1992) Graft versus host disease following allogeneic bone marrow transplantation. Current Opinion in Immunology 4:5, 571-576
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