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Thalidomide for hereditary haemorrhagic telangiectasia
Comment
Recurrent and severe epistaxis is the most common presentation of hereditary haemorrhagic telangiectasia, a rare autosomal dominant bleeding disorder characterised by mucocutaneous telangectasias and arteriovenous malformations.1,2 The onset of this severe symptom can lead to anaemia requiring frequent intravenous infusions of iron and, often, transfusion of red blood cells. Several approaches have been attempted to manage the nosebleeds of patients with hereditary haemorrhagic telangiectasia, including compression techniques, bilateral embolisation, and surgical arterial ligation, in addition to other, less commonly applied, treatments, such as laser therapy, sclerosing agents, electrocauterisation, and septodermoplasty.3 Adjuvant medical treatments include the administration of oestrogens, progestogens, and antifibrinolytic agents such as tranexamic acid.4 Nevertheless, most of these measures are only palliative and the results are largely unsatisfactory, so patients with hereditary haemorrhagic telangiectasia and severe nosebleeds usually face important impediments to daily activities and have a poor quality of life.5 Because abnormal angiogenesis has been implicated in the pathogenesis of hereditary haemorrhagic telangiectasia, research has been focused on the potential role of anti-angiogenic drugs such as bevacizumab and thalidomide. Systemic and topical use of bevacizumab, a monoclonal antibody antagonist of VEGF, has been investigated in a small number of patients with hereditary haemorrhagic telangiectasia who had severe epistaxis, yielding controversial outcomes.5 Thalidomide is a drug that has been known for more than 60 years, which has received renewed interest as an anti-cancer treatment for multiple myeloma because of its anti-angiogenic properties.6 A few case reports suggested that this drug, at a dose between 50 and 100 mg per day, might be useful to control refractory gastrointestinal bleeding, improve clinical outcomes, and reduce the need for transfusions in patients with von Willebrand disease-associated angiodysplasia, a disorder similar to hereditary haemorrhagic telangiectasia.7 However, research about thalidomide in hereditary haemorrhagic telangiectasiaassociated severe epistaxis has so far been restricted to a few anecdotal cases.8 A systematic review8 that included 21 patients from six studies reported a benefit of www.thelancet.com/haematology Vol 2 November 2015
thalidomide treatment for most patients (ie, reduction of severity, frequency, and duration of nosebleeds; reduction of blood transfusion requirements; and increased median haemoglobin concentrations). A phase 2 study from Rosangela Invernizzi and colleagues in The Lancet Haematology brings a substantial advance in this topic.9 In this clinical dose-escalation trial the researchers enrolled 31 patients with hereditary haemorrhagic telangiectasia and severe recurrent epistaxis. The patients received thalidomide at a starting daily dose of 50 mg, which was progressively increased up to 200 mg/day if they had no response. After a median follow-up of 15·9 months, the low dose of thalidomide (50 mg/day) was highly effective in reduction of the frequency, intensity, and duration of nose bleeds in 25 (81%) of 31 of patients, whereas all the remaining patients who were initially non-responders (six [19%] patients) had a response at increased doses of thalidomide (100–150 mg/day). Notably, the treatment significantly increased patients’ haemoglobin concentrations and prevented the need of transfusion in 20 (87%) of 23 patients who were dependent on of transfusions. Furthermore, the median time to relapse after the end of treatment with thalidomide was more than 6 months, which is consistent with the theory that the action of thalidomide is not only limited to the direct inhibition of endothelial cell proliferation, but also includes the induction of maturation of blood vessels that become more durable and less prone to bleeding.10 Overall, the results from the study by Invernizzi and colleagues, the largest clinical trial that has been done so far in this subject, are intriguing and suggest a potential role for this drug in a haemorrhagic disorder that is characterised by having very few therapeutic options available. Further trials with more patients are needed to assess the long-term safety and efficacy and the effects of thalidomide treatment on quality of life to confirm these preliminary, but interesting, data.
The Power of Forever Photography
Thalidomide for hereditary haemorrhagic telangiectasia
Published Online October 27, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00222-7 See Articles page e465
*Massimo Franchini, Giuseppe Lippi Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantova 46100, Italy (MF); Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy (GL) [email protected]
e457
Comment
We declare no competing interests. 1 2 3 4
5
6
e458
Sharathkumar AA, Shapiro A. Hereditary haemorrhagic telangiectasia. Haemophilia 2008; 14: 1269–80. Shovlin CL. Hereditary hemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 2010; 24: 203–19. Geisthoff UW, Fiorella ML, Fiorella R. Treatment of recurrent epistaxis in HHT. Curr Pharm Des 2006; 12: 1237–42. Sabbà C, Gallitelli M, Palasciano G. Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345: 926. Zarrabeitia R, Albiñana V, Salcedo M, Señaris-Gonzalez B, Fernandez-Forcelledo JL, Botella LM. A review on clinical management and pharmacological therapy on hereditary haemorrhagic telangiectasia (HHT). Curr Vasc Pharmacol 2010; 8: 473–81. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011; 364: 1046–60.
7 8
9
10
Franchini M, Mannucci PM. Gastrointestinal angiodysplasia and bleeding in von Willebrand disease. Thromb Haemost 2014; 112: 427–31. Franchini M, Frattini F, Crestani S, Bonfanti C. Novel treatments for epistaxis in hereditary hemorrhagic telangectasia: a systematic review of the clinical experience with thalidomide. J Thromb Thrombolysis 2013; 36: 355–57. Invernizzi R, Quaglia F, Klersy C, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a prospective phase 2 study. Lancet Haematol 2015; published online Oct 27. http://dx.doi.org/10.1016/S23523026(15)00195-7. Lebrin F, Srun S, Raymond K, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010; 16: 420–28.
www.thelancet.com/haematology Vol 2 November 2015
Recurrent and severe epistaxis is the most common presentation of hereditary haemorrhagic telangiectasia, a rare autosomal dominant bleeding disorder characterised by mucocutaneous telangectasias and arteriovenous malformations.1,2 The onset of this severe symptom can lead to anaemia requiring frequent intravenous infusions of iron and, often, transfusion of red blood cells. Several approaches have been attempted to manage the nosebleeds of patients with hereditary haemorrhagic telangiectasia, including compression techniques, bilateral embolisation, and surgical arterial ligation, in addition to other, less commonly applied, treatments, such as laser therapy, sclerosing agents, electrocauterisation, and septodermoplasty.3 Adjuvant medical treatments include the administration of oestrogens, progestogens, and antifibrinolytic agents such as tranexamic acid.4 Nevertheless, most of these measures are only palliative and the results are largely unsatisfactory, so patients with hereditary haemorrhagic telangiectasia and severe nosebleeds usually face important impediments to daily activities and have a poor quality of life.5 Because abnormal angiogenesis has been implicated in the pathogenesis of hereditary haemorrhagic telangiectasia, research has been focused on the potential role of anti-angiogenic drugs such as bevacizumab and thalidomide. Systemic and topical use of bevacizumab, a monoclonal antibody antagonist of VEGF, has been investigated in a small number of patients with hereditary haemorrhagic telangiectasia who had severe epistaxis, yielding controversial outcomes.5 Thalidomide is a drug that has been known for more than 60 years, which has received renewed interest as an anti-cancer treatment for multiple myeloma because of its anti-angiogenic properties.6 A few case reports suggested that this drug, at a dose between 50 and 100 mg per day, might be useful to control refractory gastrointestinal bleeding, improve clinical outcomes, and reduce the need for transfusions in patients with von Willebrand disease-associated angiodysplasia, a disorder similar to hereditary haemorrhagic telangiectasia.7 However, research about thalidomide in hereditary haemorrhagic telangiectasiaassociated severe epistaxis has so far been restricted to a few anecdotal cases.8 A systematic review8 that included 21 patients from six studies reported a benefit of www.thelancet.com/haematology Vol 2 November 2015
thalidomide treatment for most patients (ie, reduction of severity, frequency, and duration of nosebleeds; reduction of blood transfusion requirements; and increased median haemoglobin concentrations). A phase 2 study from Rosangela Invernizzi and colleagues in The Lancet Haematology brings a substantial advance in this topic.9 In this clinical dose-escalation trial the researchers enrolled 31 patients with hereditary haemorrhagic telangiectasia and severe recurrent epistaxis. The patients received thalidomide at a starting daily dose of 50 mg, which was progressively increased up to 200 mg/day if they had no response. After a median follow-up of 15·9 months, the low dose of thalidomide (50 mg/day) was highly effective in reduction of the frequency, intensity, and duration of nose bleeds in 25 (81%) of 31 of patients, whereas all the remaining patients who were initially non-responders (six [19%] patients) had a response at increased doses of thalidomide (100–150 mg/day). Notably, the treatment significantly increased patients’ haemoglobin concentrations and prevented the need of transfusion in 20 (87%) of 23 patients who were dependent on of transfusions. Furthermore, the median time to relapse after the end of treatment with thalidomide was more than 6 months, which is consistent with the theory that the action of thalidomide is not only limited to the direct inhibition of endothelial cell proliferation, but also includes the induction of maturation of blood vessels that become more durable and less prone to bleeding.10 Overall, the results from the study by Invernizzi and colleagues, the largest clinical trial that has been done so far in this subject, are intriguing and suggest a potential role for this drug in a haemorrhagic disorder that is characterised by having very few therapeutic options available. Further trials with more patients are needed to assess the long-term safety and efficacy and the effects of thalidomide treatment on quality of life to confirm these preliminary, but interesting, data.
The Power of Forever Photography
Thalidomide for hereditary haemorrhagic telangiectasia
Published Online October 27, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00222-7 See Articles page e465
*Massimo Franchini, Giuseppe Lippi Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantova 46100, Italy (MF); Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy (GL) [email protected]
e457
Comment
We declare no competing interests. 1 2 3 4
5
6
e458
Sharathkumar AA, Shapiro A. Hereditary haemorrhagic telangiectasia. Haemophilia 2008; 14: 1269–80. Shovlin CL. Hereditary hemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 2010; 24: 203–19. Geisthoff UW, Fiorella ML, Fiorella R. Treatment of recurrent epistaxis in HHT. Curr Pharm Des 2006; 12: 1237–42. Sabbà C, Gallitelli M, Palasciano G. Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345: 926. Zarrabeitia R, Albiñana V, Salcedo M, Señaris-Gonzalez B, Fernandez-Forcelledo JL, Botella LM. A review on clinical management and pharmacological therapy on hereditary haemorrhagic telangiectasia (HHT). Curr Vasc Pharmacol 2010; 8: 473–81. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011; 364: 1046–60.
7 8
9
10
Franchini M, Mannucci PM. Gastrointestinal angiodysplasia and bleeding in von Willebrand disease. Thromb Haemost 2014; 112: 427–31. Franchini M, Frattini F, Crestani S, Bonfanti C. Novel treatments for epistaxis in hereditary hemorrhagic telangectasia: a systematic review of the clinical experience with thalidomide. J Thromb Thrombolysis 2013; 36: 355–57. Invernizzi R, Quaglia F, Klersy C, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a prospective phase 2 study. Lancet Haematol 2015; published online Oct 27. http://dx.doi.org/10.1016/S23523026(15)00195-7. Lebrin F, Srun S, Raymond K, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010; 16: 420–28.
www.thelancet.com/haematology Vol 2 November 2015