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Thromb Haemost 2011; 106(04): 641-645
DOI: 10.1160/TH11-04-0274
DOI: 10.1160/TH11-04-0274
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Phase II prospective open-label trial of recombinant interleukin-11 in women with mild von Willebrand disease and refractory menorrhagia[*]
Financial support: This study was supported by HHS Federal Region III Hemophilia Treatment Centers, Grant #1-H-30-MC-00038–01; the Center for Diseases Control Prevention of Complications of Hemophilia Grant U10DD000193; the Pennsylvania Department of Health State SAP #04100000330 (MVR); and CTRC/CTSI grant: NIH/NCRR/CTSA UL-1 RR024153; Wyeth, Inc., Grant #102344; and Clinical Trials.gov NCT 00524342.
Further Information
Publication History
Received:
27 April 2011
Accepted after major revision:
08 July 2011
Publication Date:
15 December 2017 (online)
Summary
Lack of effective treatment for menorrhagia is the greatest unmet healthcare need in women with von Willebrand disease (VWD). We conducted a single-centre phase II clinical trial to determine efficacy and safety of recombinant IL-11 (rhIL-11, Neumega®) given subcutaneously for up to seven days during six consecutive menstrual cycles each in seven women with mild VWD and menorrhagia refractory to haemostatic or hormonal agents. rhIL-11 reduced menstrual bleeding severity as measured by pictorial blood assessment chart (PBAC) ≥50% (to <100) in 71% of subjects, cycle severity ≥50% in 71%, and bleeding duration ≥2 days in 85%, all p≤0.01. After rhIL-11, plasma VWF:RCo increased 1.1-fold, but did not correlate with PBAC, r=0.116, bleeding duration, r=0.318, or cycle severity, r=-0.295, or hsCRP, r=-0.003, all p>0.05. Platelet VWF mRNA expression by quantitative PCR increased mean four-fold (1.0–13.5). rhIL-11 was well tolerated with grade 1 or less fluid retention, flushing, conjunctival erythema, and local bruising. In summary, rhIL-11 reduces menorrhagia safely and warrants further study.
Notes
* Clinical trial registration number: NCT 00524342.
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References
- 1 Ragni MV, Bontempo FA, Cortese-Hassett AL. Von Willebrand disease and bleeding in women. Haemophilia 1999; 5: 313-317.
- 2 James A, Ragni MV, Picozzi V. ASH Special Educational Symposium: Bleeding Disorders in Premenopausal Women: Another Public Health Crisis for Hematology. Hematology 2006; 474-485.
- 3 Kouides PA, Kadir RA. Menorrhagia associated with laboratory abnormalities of hemostasis: epidemiological, diagnostic, and therapeutic aspects. J Thromb Haemost 2007; 5 (Suppl. 01) 175-182.
- 4 Kadir RA, Chi C. Women and von Willebrand Disease: Controversies in diagnosis and management. Sem Thromb Haemost 2006; 32: 605-615.
- 5 Kadir RA, Edlund M, von Mackensen S. The impact of menstrual disorders on quality of life in women with inherited bleeding disorders. Haemophilia 2010; 16: 832-839.
- 6 Mannucci PM. Desmopressin in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
- 7 Rodeghiero F, Castaman G, Tosetto A. et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international multicenter study. J Thromb Haemost 2005; 3: 2619-2626.
- 8 Kadir RA, Lee CA, Sabin CA. et al. DDAVP nasal spray for treatment of menorrhagia in women with inherited bleeding disorders: a randomized placebo-controlled crossover study. Haemophilia 2002; 8: 787-793.
- 9 Byams VR, Baker J, Brown DL. et al. Baseline characteristics of females with bleeding disorders receiving care in the U.S. HTC Network. National Conf on Blood Disorders in Public Health 2010; 77: E3. Abstract 4.
- 10 Kouides PA, Byams VR, Philipp CS. et al. Multisite management study of monorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol 2009; 145: 212-220.
- 11 Nichols WL, Hultin MB, James AH. et al. Von Willebrand Disease (VWD): Evidence-based diagnosis and management guidelines, the National Heart Lung and Blood Institute (NHLBI) Expert Panel Report (USA). Haemophilia 2008; 14: 171-232.
- 12 Medical Product Safety.. In Healthy People 2010: A Systematic Approach to Health Improvement. 2003; 17: 3-19.
- 13 Tepler I, Elias L, Smith JW. et al. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood 1996; 87: 3607-3614.
- 14 Gordon M, Kaye JA, McCaskill-Steffens WJ. et al. A phase I trial of recombinant human interleukin-11 (Neumega, rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Blood 1996; 87: 3615-3624.
- 15 Ragni MV, Jankowitz RC, Chapman HL. et al. A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease. Haemophilia 2008; 14: 968-977.
- 16 Janssen CAH, Scholten PC, Heintz APM.. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol 1995; 85: 977-982.
- 17 Haberichter SL, Merricks EP, Fahs SA. et al. Reestablishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 2005; 105: 145-152.
- 18 Benson RE, Catalfamo JL, Dodds WJ. A multispecies enzyme-linked immunosorbent assay for von Willebrand factor. J Lab Clin Med 1992; 119: 420-427.
- 19 Brouland JP, Egan T, Roussi J. et al. In vivo regulation of von Willebrand factor synthesis: von Willebrand factor production in endothelial cells after lung transplantation between normal pigs and von Willebrand factor-deficient pigs. Arterioscler Thromb Vasc Biol 1999; 19: 3055-3062.
- 20 Nichols TC, Bellinger DA, Reddick RL. et al. The roles of von Willebrand factor and factor VIII in arterial thrombosis: studies in canine von Willebrand disease and hemophilia A. Blood 1993; 81: 2644-2651.
- 21 Estey EH, Thall PF. New designs for phase 2 clinical trials. Blood 2003; 102: 442-448.
- 22 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). version 4.03, June 14, 2010. Available at: http://ctep.cancer.gov/forms/CTCAEv4.pdf
- 23 Kyrtle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-462.
- 24 Edlund M, Blomback M, He S. On the correlation between local fibrinlytic activity in menstrual fluid and total blood loss during menstruation and effects of desmopressin. Blood Coag Fibriniolysis 2003; 14: 593-598.
- 25 Luxembourg B, Schmitt J, Humpich M. et al. Cardiovascular risk factors in idiopathic compared to risk-associated venous thromboembolism: a focus on fibrinogen, factor VIII, and high-sensitivity C-reactive protein (hs-CRP). Thromb Haemost 2009; 102: 668-675.
- 26 Bach J, Haubelt H, Hellstern P. Sources of variation in factor VIII, von Willebrand factor and fibrinogen measurements. Thromb Res 2010; 126: e188-195.
- 27 Ragni MV, Kessler CM. Hemophilia and Von Willebrand Disease Subcommittee: Four Randomized Controlled Clinical Trial Concepts. State of the Science Symposium in Transfusion Medicine, Hemostasis and Thrombosis (SoS-TMH), NHLBI. Bethesda, MD: September 14 2009