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Desensitization to Thalidomide in a Patient with Multiple Myeloma
Case Report Desensitization to Thalidomide in a Patient with Multiple Myeloma Eleonora Nucera,1 Domenico Schiavino,1 Stefan Hohaus,2 Giuseppe Leone,2 Alessandro Buonomo,1 Carla Lombardo,1 Giampiero Patriarca1
Abstract Cutaneous reactions to thalidomide have been noted in approximately 46% of patients treated with this drug. We describe a case of a 65-year-old woman with multiple myeloma who developed fever and a generalized, itchy maculopapular rash after a 2-day treatment with thalidomide 100 mg orally. Skin prick and patch test results with thalidomide were negative, while the oral provocation test results were positive. Because thalidomide was necessary for the patient, she underwent an oral desensitization protocol, and on the fifth day, she could tolerate 100 mg of oral thalidomide. To our knowledge, this is the first report in the literature regarding this topic.
Clinical Lymphoma & Myeloma, Vol. 8, No. 3, 176-178, 2008; DOI: 10.3816/CLM.2008.n.022 Key words: Nonallergic drug hypersensitivity, Oral tolerance induction, Patch tests
Introduction Thalidomide is a synthetic glutamic acid derivative currently used to treat multiple myeloma (MM)1 and other immunologic disorders such as erythema nodosum leprosum and oral ulcers in Behçet's disease. Thalidomide probably has several molecular targets; for example, it inhibits angiogenesis2 and also has anti–tumor necrosis factor–α activity.3 Thalidomide was introduced for the treatment of MM in the late 1990s, and its introduction represented a major advance in the therapy of this disease. The addition of thalidomide to the conventional melphalan/prednisone combination resulted in an increase of response rates and prolonged survival in elderly patients with MM.4 The combination of thalidomide and dexamethasone has become an effective alternative to chemotherapeutic regimens as induction therapy for younger patients with MM who are candidates for subsequent highdose therapy with autologous transplantation.5-7 However, thalidomide use is associated with several side effects: Somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious.8 1Department of Allergology 2Institute of Hematology
Catholic University, Rome, Italy Submitted: Jul 13, 2007; Revised: Dec 18, 2007; Accepted: Jan 7, 2008 Address for correspondence: Giampiero Patriarca, MD, Department of Allergology, Catholic University, Policlinico Gemelli, Largo Gemelli, 8, 00168 Rome, Italy Fax: 39-06-30-156-999; e-mail: [email protected]
Minor-to-moderate cutaneous reactions to this drug have been noted in approximately 46% of patients receiving thalidomide.9 The most common is an itchy maculopapular rash starting on the trunk and extending to the back and proximal limbs that does not appear to be dose related. Temporary discontinuation of thalidomide leads to resolution of the rash and usually permits re-administration at a lower dose.8 Severe skin reactions such as the life-threatening Stevens-Johnson syndrome occur in < 1% of patients treated with thalidomide.10 Some authors suggested that prophylactic treatment with corticosteroids could prevent cutaneous reactions to thalidomide and that this would also be effective in patients who have already experienced previous adverse cutaneous reactions to this drug.11
Case Report We describe a case of a 65-year-old woman diagnosed with symptomatic immunoglobulin Gλ MM in February 2006. She was initially treated with bisphosphonates and prednisone for hypercalcemia associated with mild renal failure and hydration and also with transfusional support for anemia. Her treatment plan included therapy with thalidomide/dexamethasone followed by high-dose cyclophosphamide and stem cell collection for double autologous transplantation after high-dose melphalan. After a 2day treatment with oral thalidomide 100 mg daily combined with oral dexamethasone 40 mg, she developed fever and a generalized, itchy maculopapular rash starting on the trunk and quickly extending to the limbs. Concurrent treatment consisted of insulin for type II diabetes and atenolol, lacidipine, and valsartan/ hydrochlorothiazide for hypertension. The patient had also
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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started supportive medication with erythropoietin, enoxaparin, omeprazole, and allopurinol. Allopurinol and thalidomide were withdrawn and symptoms promptly receded. After 4 days, the patient restarted therapy with thalidomide but presented again with fever, hypotension, and an intense generalized rash, resulting in the withdrawal of thalidomide. She received 1 cycle with melphalan and prednisone as alternative treatment for MM. The patient (with no clinical history of drug or other allergies) then underwent allergy testing with thalidomide and dexamethasone. Skin tests were carried out on the volar surface of the forearm. Thalidomide was “prick-by-prick” tested only, using a powdered tablet dissolved in saline,12 and an intradermal test with dexamethasone at a concentration of 0.04 mg/mL was also performed. Readings were taken after 20 minutes and after 48 hours in case any delayed reaction occurred. Histamine as positive control and saline as negative control were used. Immediate reactions ≥ 3 mm greater than negative control for prick tests and ≥ 5 mm greater than control for intradermal tests were considered positive. Patch tests were performed using the same drugs used for skin tests according to the indications of the European Network for Drug Allergy and the European Academy of Allergology and Clinical Immunology interest group on drug hypersensitivity. Patches were applied in the interscapular region and evaluated at 48 hours and 72 hours according to the recommendations of the American Academy of Dermatology.13 Commercially available self-adhesive anallergic gauze strips were used as supports. After the skin tests, we performed an open oral provocation test with thalidomide in a day-hospital regimen as follows: On the first day, the patient received a cumulative dose of 10 mg by administering 1, 2, 3, and 4 mg every 30 minutes; on the second day, she received 100 mg of thalidomide by administering 25, 25, and 50 mg every 30 minutes. At the end of the test, the patient was observed for 6 hours in case any reaction occurred. The desensitization protocol was performed in a 5-day hospitalization regimen, administering increasing doses of different dilutions (the tablet powder was dissolved in water) of thalidomide every 30 minutes until the final dose of 100 mg (Table 1). We performed this treatment using premedication with oral loratadine 10 mg daily to reduce the risk of a hypersensitivity reaction. The procedure was in accordance with the ethical standards of the responsible committees on human experimentation and with the Helsinki Declaration of 1975 as revised in 2000. An informed written consent was obtained from the patient before the procedure. Skin prick test and patch test results with thalidomide and dexamethasone were negative, whereas the oral provocation test result with thalidomide was positive; in fact, the patient experienced an itchy erythematous rash on the abdomen and legs after a cumulative dose of 100 mg of thalidomide. Symptoms receded after intramuscular chlorpheniramine 10 mg was administered twice a day for 7 days. The diagnosis was determined to be a nonallergic hypersensitivity reaction to thalidomide. Because thalidomide represented an essential drug in the treatment program of the patient, we then decided to perform an oral tolerance induction with this drug according to our
Table 1 Protocol of Oral Tolerance Induction with Thalidomide Day
Doses
1
0.1 μg, 0.2 μg, 0.3 μg, 0.4 μg
2
1 μg, 2 μg, 3 μg, 4 μg
3
0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg
4
1 mg, 2 mg, 3 mg, 4 mg, 10 mg, 20 mg, 30 mg, 40 mg
5
1 Tablet (100 mg)
previous experiences.14-19 During the desensitization protocol, the patient did not experience any adverse reaction, and on the fifth day, she was able to reach the therapeutic dose of thalidomide 100 mg per day. She was then challenged again in an open way without loratadine and continued taking thalidomide at home with no side effects for 3 months with 4day cycles of dexamethasone. She subsequently completed her treatment program with high-dose cyclophosphamide (4 g/m2) and 2 cycles of high-dose melphalan with autologous stem cell transplantation and had a partial remission. Two months before the second autologous stem cell transplantation, the patient had interrupted treatment with thalidomide. After 3 months from the transplantation, she was seen again in our allergy department because she needed to be treated with thalidomide again and underwent a further oral provocation test to assess tolerance. Despite a 5-month interruption, the patient could still tolerate thalidomide with no side effects, and she is currently on oral thalidomide maintenance therapy (100 mg daily).
Discussion Desensitization for drug allergies is the induction of temporary clinical unresponsiveness to drug antigens. The gradual reintroduction of small doses of drug antigen at fixed time intervals allows for the delivery of the full therapeutic dose. The exact mechanism of tolerance induction is still poorly understood; it has been hypothesized that low, continuous, incremental doses of antigen might have resulted in univalent occupancy of receptors so that antibody or immune cells cannot be crosslinked by higher doses of the drug. Such a mechanism has been demonstrated in other situations, especially in patients allergic to β-lactam.20 Recent studies of in vitro rapid antigen desensitization implicate basophils and mast cells as cellular targets as well as Syk (a signal-transducing molecule)21 and STAT6 (a signal transducer and transcription activator responsible for the transcription of interleukin (IL)–4 and IL-13).22 Also, nonallergic drug hypersensitivity reactions can be treated with desensitization, but there are no certainties about the pathogenic mechanism.
Conclusion To our knowledge, this is the first report of oral desensitization with thalidomide. Previous articles report on the usefulness of corticosteroids with thalidomide to prevent adverse
Clinical Lymphoma & Myeloma June 2008
•
177
Desensitization to Thalidomide in MM hypersensitivity reactions or to allow patients with previous adverse reactions to continue their treatment,3 but our patient developed an adverse reaction despite premedication with dexamethasone. When corticosteroids are not efficacious to prevent hypersensitivity reactions or when their use is not recommended for the patient (eg, in the case of diabetes), a desensitization protocol can be a safe and effective way to continue treatment without reducing the therapeutic dose. Of course, other studies are needed to assess the efficacy of this protocol.
References 1. Shingal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341:1565-71. 2. D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994; 91:4082-5. 3. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173:699-703. 4. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Italian Multiple Myeloma Network, GIMEMA. Lancet 2006; 367:825-31. 5. Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Bologna 2002 study. Blood 2005; 106:35-9. 6. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24:431-6. 7. Richardson P, Anderson K. Thalidomide and dexamethasone: a new standard of care for initial therapy in multiple myeloma. J Clin Oncol 2006; 24:334-6.
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8. Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med 2004; 117:508-15. 9. Hall VC, El-Azhary RA, Bouwhuis S, et al. Dermatologic side effects of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 2003; 48:548-52. 10. Horowitz SB, Stirling AL. Thalidomide-induced toxic epidermal necrolysis. Pharmacotherapy 1999; 19:1177-80. 11. Nijsten T, Meuleman L, Schroyens W, et al. Thalidomide-induced morbilliform rush: diagnosis and continuation of therapy, premedicated with methylprednisolone. Dermatology 2002; 204:365-7. 12. Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002; 57:45-51. 13. Marks JG Jr, Belsito DV, De Leo VA, et al. American Contact Dermatitis Group patch test results 1996-1998. Arch Dermatol 2000; 136:272-3. 14. Patriarca G, Rossi M, Schiavino D, et al. Rush desensitization in heparin hypersensitivity: a case report. Allergy 1994; 49:292-4. 15. Patriarca G, Schiavino D, Nucera E, et al. Successful desensitization of a child with desferrioxamine hypersensitivity. J Investig Allergol Clin Immunol 1995; 5:294-5. 16. Nucera E, Schiavino D, Buonomo A, et al. Tolerance induction to cotrimoxazole. Allergy 2000; 55:681-2. 17. Nucera E, Roncallo C, Masini L, et al. Successful tolerance induction to spiramycin in pregnancy. Scand J Infect Dis 2002; 34:550-1. 18. Nucera E, Schiavino D, Merendino E, et al. Successful fluorescein desensitization. Allergy 2003; 58:458. 19. Nucera E, Schiavino D, Pollastrini E, et al. Tolerance induction to rofecoxib in a patient with Bartter’s syndrome. Allergy 2004; 59:788-9. 20. Sullivan TJ. Drug allergy. In: Middleton E Jr, Redd CE, Ellis EF, et al (eds). Allergy: Principles and Practice. Vol II. 4th Ed. St. Louis, MO: Mosby-Yearbook Inc; 1993:1726-46. 21. Kepley CL. Antigen-induced reduction in mast cell and basophil functional responses due to reduced Syk proteins level. Int Arch Allergy Immunol 2005; 138:29-39. 22. Morales AR, Shah N, Castells M. Antigen-IgE desensitization in signal transducer and activator of transcription 6-deficient mast cells by suboptimal doses of antigen. Ann Allergy Asthma Immunol 2005; 94:575-80.
Abstract Cutaneous reactions to thalidomide have been noted in approximately 46% of patients treated with this drug. We describe a case of a 65-year-old woman with multiple myeloma who developed fever and a generalized, itchy maculopapular rash after a 2-day treatment with thalidomide 100 mg orally. Skin prick and patch test results with thalidomide were negative, while the oral provocation test results were positive. Because thalidomide was necessary for the patient, she underwent an oral desensitization protocol, and on the fifth day, she could tolerate 100 mg of oral thalidomide. To our knowledge, this is the first report in the literature regarding this topic.
Clinical Lymphoma & Myeloma, Vol. 8, No. 3, 176-178, 2008; DOI: 10.3816/CLM.2008.n.022 Key words: Nonallergic drug hypersensitivity, Oral tolerance induction, Patch tests
Introduction Thalidomide is a synthetic glutamic acid derivative currently used to treat multiple myeloma (MM)1 and other immunologic disorders such as erythema nodosum leprosum and oral ulcers in Behçet's disease. Thalidomide probably has several molecular targets; for example, it inhibits angiogenesis2 and also has anti–tumor necrosis factor–α activity.3 Thalidomide was introduced for the treatment of MM in the late 1990s, and its introduction represented a major advance in the therapy of this disease. The addition of thalidomide to the conventional melphalan/prednisone combination resulted in an increase of response rates and prolonged survival in elderly patients with MM.4 The combination of thalidomide and dexamethasone has become an effective alternative to chemotherapeutic regimens as induction therapy for younger patients with MM who are candidates for subsequent highdose therapy with autologous transplantation.5-7 However, thalidomide use is associated with several side effects: Somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious.8 1Department of Allergology 2Institute of Hematology
Catholic University, Rome, Italy Submitted: Jul 13, 2007; Revised: Dec 18, 2007; Accepted: Jan 7, 2008 Address for correspondence: Giampiero Patriarca, MD, Department of Allergology, Catholic University, Policlinico Gemelli, Largo Gemelli, 8, 00168 Rome, Italy Fax: 39-06-30-156-999; e-mail: [email protected]
Minor-to-moderate cutaneous reactions to this drug have been noted in approximately 46% of patients receiving thalidomide.9 The most common is an itchy maculopapular rash starting on the trunk and extending to the back and proximal limbs that does not appear to be dose related. Temporary discontinuation of thalidomide leads to resolution of the rash and usually permits re-administration at a lower dose.8 Severe skin reactions such as the life-threatening Stevens-Johnson syndrome occur in < 1% of patients treated with thalidomide.10 Some authors suggested that prophylactic treatment with corticosteroids could prevent cutaneous reactions to thalidomide and that this would also be effective in patients who have already experienced previous adverse cutaneous reactions to this drug.11
Case Report We describe a case of a 65-year-old woman diagnosed with symptomatic immunoglobulin Gλ MM in February 2006. She was initially treated with bisphosphonates and prednisone for hypercalcemia associated with mild renal failure and hydration and also with transfusional support for anemia. Her treatment plan included therapy with thalidomide/dexamethasone followed by high-dose cyclophosphamide and stem cell collection for double autologous transplantation after high-dose melphalan. After a 2day treatment with oral thalidomide 100 mg daily combined with oral dexamethasone 40 mg, she developed fever and a generalized, itchy maculopapular rash starting on the trunk and quickly extending to the limbs. Concurrent treatment consisted of insulin for type II diabetes and atenolol, lacidipine, and valsartan/ hydrochlorothiazide for hypertension. The patient had also
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Clinical Lymphoma & Myeloma June 2008
started supportive medication with erythropoietin, enoxaparin, omeprazole, and allopurinol. Allopurinol and thalidomide were withdrawn and symptoms promptly receded. After 4 days, the patient restarted therapy with thalidomide but presented again with fever, hypotension, and an intense generalized rash, resulting in the withdrawal of thalidomide. She received 1 cycle with melphalan and prednisone as alternative treatment for MM. The patient (with no clinical history of drug or other allergies) then underwent allergy testing with thalidomide and dexamethasone. Skin tests were carried out on the volar surface of the forearm. Thalidomide was “prick-by-prick” tested only, using a powdered tablet dissolved in saline,12 and an intradermal test with dexamethasone at a concentration of 0.04 mg/mL was also performed. Readings were taken after 20 minutes and after 48 hours in case any delayed reaction occurred. Histamine as positive control and saline as negative control were used. Immediate reactions ≥ 3 mm greater than negative control for prick tests and ≥ 5 mm greater than control for intradermal tests were considered positive. Patch tests were performed using the same drugs used for skin tests according to the indications of the European Network for Drug Allergy and the European Academy of Allergology and Clinical Immunology interest group on drug hypersensitivity. Patches were applied in the interscapular region and evaluated at 48 hours and 72 hours according to the recommendations of the American Academy of Dermatology.13 Commercially available self-adhesive anallergic gauze strips were used as supports. After the skin tests, we performed an open oral provocation test with thalidomide in a day-hospital regimen as follows: On the first day, the patient received a cumulative dose of 10 mg by administering 1, 2, 3, and 4 mg every 30 minutes; on the second day, she received 100 mg of thalidomide by administering 25, 25, and 50 mg every 30 minutes. At the end of the test, the patient was observed for 6 hours in case any reaction occurred. The desensitization protocol was performed in a 5-day hospitalization regimen, administering increasing doses of different dilutions (the tablet powder was dissolved in water) of thalidomide every 30 minutes until the final dose of 100 mg (Table 1). We performed this treatment using premedication with oral loratadine 10 mg daily to reduce the risk of a hypersensitivity reaction. The procedure was in accordance with the ethical standards of the responsible committees on human experimentation and with the Helsinki Declaration of 1975 as revised in 2000. An informed written consent was obtained from the patient before the procedure. Skin prick test and patch test results with thalidomide and dexamethasone were negative, whereas the oral provocation test result with thalidomide was positive; in fact, the patient experienced an itchy erythematous rash on the abdomen and legs after a cumulative dose of 100 mg of thalidomide. Symptoms receded after intramuscular chlorpheniramine 10 mg was administered twice a day for 7 days. The diagnosis was determined to be a nonallergic hypersensitivity reaction to thalidomide. Because thalidomide represented an essential drug in the treatment program of the patient, we then decided to perform an oral tolerance induction with this drug according to our
Table 1 Protocol of Oral Tolerance Induction with Thalidomide Day
Doses
1
0.1 μg, 0.2 μg, 0.3 μg, 0.4 μg
2
1 μg, 2 μg, 3 μg, 4 μg
3
0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg
4
1 mg, 2 mg, 3 mg, 4 mg, 10 mg, 20 mg, 30 mg, 40 mg
5
1 Tablet (100 mg)
previous experiences.14-19 During the desensitization protocol, the patient did not experience any adverse reaction, and on the fifth day, she was able to reach the therapeutic dose of thalidomide 100 mg per day. She was then challenged again in an open way without loratadine and continued taking thalidomide at home with no side effects for 3 months with 4day cycles of dexamethasone. She subsequently completed her treatment program with high-dose cyclophosphamide (4 g/m2) and 2 cycles of high-dose melphalan with autologous stem cell transplantation and had a partial remission. Two months before the second autologous stem cell transplantation, the patient had interrupted treatment with thalidomide. After 3 months from the transplantation, she was seen again in our allergy department because she needed to be treated with thalidomide again and underwent a further oral provocation test to assess tolerance. Despite a 5-month interruption, the patient could still tolerate thalidomide with no side effects, and she is currently on oral thalidomide maintenance therapy (100 mg daily).
Discussion Desensitization for drug allergies is the induction of temporary clinical unresponsiveness to drug antigens. The gradual reintroduction of small doses of drug antigen at fixed time intervals allows for the delivery of the full therapeutic dose. The exact mechanism of tolerance induction is still poorly understood; it has been hypothesized that low, continuous, incremental doses of antigen might have resulted in univalent occupancy of receptors so that antibody or immune cells cannot be crosslinked by higher doses of the drug. Such a mechanism has been demonstrated in other situations, especially in patients allergic to β-lactam.20 Recent studies of in vitro rapid antigen desensitization implicate basophils and mast cells as cellular targets as well as Syk (a signal-transducing molecule)21 and STAT6 (a signal transducer and transcription activator responsible for the transcription of interleukin (IL)–4 and IL-13).22 Also, nonallergic drug hypersensitivity reactions can be treated with desensitization, but there are no certainties about the pathogenic mechanism.
Conclusion To our knowledge, this is the first report of oral desensitization with thalidomide. Previous articles report on the usefulness of corticosteroids with thalidomide to prevent adverse
Clinical Lymphoma & Myeloma June 2008
•
177
Desensitization to Thalidomide in MM hypersensitivity reactions or to allow patients with previous adverse reactions to continue their treatment,3 but our patient developed an adverse reaction despite premedication with dexamethasone. When corticosteroids are not efficacious to prevent hypersensitivity reactions or when their use is not recommended for the patient (eg, in the case of diabetes), a desensitization protocol can be a safe and effective way to continue treatment without reducing the therapeutic dose. Of course, other studies are needed to assess the efficacy of this protocol.
References 1. Shingal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341:1565-71. 2. D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994; 91:4082-5. 3. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173:699-703. 4. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Italian Multiple Myeloma Network, GIMEMA. Lancet 2006; 367:825-31. 5. Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Bologna 2002 study. Blood 2005; 106:35-9. 6. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24:431-6. 7. Richardson P, Anderson K. Thalidomide and dexamethasone: a new standard of care for initial therapy in multiple myeloma. J Clin Oncol 2006; 24:334-6.
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8. Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med 2004; 117:508-15. 9. Hall VC, El-Azhary RA, Bouwhuis S, et al. Dermatologic side effects of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 2003; 48:548-52. 10. Horowitz SB, Stirling AL. Thalidomide-induced toxic epidermal necrolysis. Pharmacotherapy 1999; 19:1177-80. 11. Nijsten T, Meuleman L, Schroyens W, et al. Thalidomide-induced morbilliform rush: diagnosis and continuation of therapy, premedicated with methylprednisolone. Dermatology 2002; 204:365-7. 12. Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002; 57:45-51. 13. Marks JG Jr, Belsito DV, De Leo VA, et al. American Contact Dermatitis Group patch test results 1996-1998. Arch Dermatol 2000; 136:272-3. 14. Patriarca G, Rossi M, Schiavino D, et al. Rush desensitization in heparin hypersensitivity: a case report. Allergy 1994; 49:292-4. 15. Patriarca G, Schiavino D, Nucera E, et al. Successful desensitization of a child with desferrioxamine hypersensitivity. J Investig Allergol Clin Immunol 1995; 5:294-5. 16. Nucera E, Schiavino D, Buonomo A, et al. Tolerance induction to cotrimoxazole. Allergy 2000; 55:681-2. 17. Nucera E, Roncallo C, Masini L, et al. Successful tolerance induction to spiramycin in pregnancy. Scand J Infect Dis 2002; 34:550-1. 18. Nucera E, Schiavino D, Merendino E, et al. Successful fluorescein desensitization. Allergy 2003; 58:458. 19. Nucera E, Schiavino D, Pollastrini E, et al. Tolerance induction to rofecoxib in a patient with Bartter’s syndrome. Allergy 2004; 59:788-9. 20. Sullivan TJ. Drug allergy. In: Middleton E Jr, Redd CE, Ellis EF, et al (eds). Allergy: Principles and Practice. Vol II. 4th Ed. St. Louis, MO: Mosby-Yearbook Inc; 1993:1726-46. 21. Kepley CL. Antigen-induced reduction in mast cell and basophil functional responses due to reduced Syk proteins level. Int Arch Allergy Immunol 2005; 138:29-39. 22. Morales AR, Shah N, Castells M. Antigen-IgE desensitization in signal transducer and activator of transcription 6-deficient mast cells by suboptimal doses of antigen. Ann Allergy Asthma Immunol 2005; 94:575-80.