Download PDF
Thromb Haemost 2013; 109(02): 248-254
DOI: 10.1160/TH12-06-0447
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Phase II prospective open-label trial of recombinant interleukin-11 in desmopressin-unresponsive von Willebrand disease and mild or moderate haemophilia A

Margaret V. Ragni
1   Department of Medicine, Division of Hematology/Oncology and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
2   Haemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA
,
Enrico M. Novelli
1   Department of Medicine, Division of Hematology/Oncology and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
2   Haemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA
,
Anila Murshed
2   Haemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA
,
Elizabeth P. Merricks
3   Department of Pathology and Laboratory Medicine/ Francis Owen Blood Research Laboratory, University of North Carolina, Chapel Hill, North Carolina, USA
,
Mark T. Kloos
3   Department of Pathology and Laboratory Medicine/ Francis Owen Blood Research Laboratory, University of North Carolina, Chapel Hill, North Carolina, USA
,
Timothy C. Nichols
3   Department of Pathology and Laboratory Medicine/ Francis Owen Blood Research Laboratory, University of North Carolina, Chapel Hill, North Carolina, USA
› Author Affiliations Financial support: The Pennsylvania Department of Health State SAP #04100000330 (MVR); and CTRC/ CTSI grant: NIH/NCRR/CTSA UL-1 RR024153; Vascular Medicine Institute, P3HVB Grant 706654 (MVR); University of Pittsburgh Provost Technology Development Fund, Grant TDF OTM 10024 (MVR), and Clinical Trials.gov NCT 00994929.
Further Information

Publication History

Received: 30 June 2012

Accepted after major revision: 14 November 2012

Publication Date:
29 November 2017 (online)

    Permissions and Reprints

Summary

Desmopressin (DDAVP) is the treatment of choice in those with mild von Willebrand disease (VWD), yet 20% are unresponsive to DDAVP, and among the 80% who respond, the response is transient, as endothelial stores are depleted after three days. We, therefore, conducted a single-center Phase II clinical trial to determine safety and biologic efficacy of recombinant interleukin-11 (rhIL-11, Neumega®) in patients with VWD unresponsive or allergic to DDAVP, or mild or moderate haemophilia A (HA). Increases in VWF:RCo were observed by 48 hours after rhIL-11, with a 1.54-fold increase by Day 4, 1.30-fold in VWD and 1.73-fold in HA. Similarly, by 48 hours, increases in VIII:C were observed, with a 1.65-fold increase by Day 4, 1.86-fold in VWD and 1.48-fold in HA. Platelet VWFmRNA expression by qPCR increased 0.81-fold but did not correlate with plasma VWF:Ag responses. rhIL-11 was well tolerated, with grade 1 or less fluid retention, flushing, conjunctival erythema, except for transient grade 3 hyponatraemia in one subject after excess fluid intake for diabetic hyperglycaemia, which resolved with fluid restriction. In summary, rhIL-11 increases VWF levels in two of four DDAVP-unresponsive or allergic VWD and F.VIII levels in four of five mild or moderate haemophilia A subjects, suggesting its potential use in treatment of these disorders.

Keywords

Clinical trial - recombinant interleukin-11 - von Willebrand disease - haemophilia A
 

  • References

  • 1 Rodeghiero F, Castaman G, Dini E. Epidemiologic investigation of the prevalence of Von Willebrand disease. Blood 1987; 69: 454-459.
    PubMedGoogle Scholar
  • 2 Ginsburg D, Sadler JE. Von Willebrand disease: a database of point mutations, insertions and deletions. Thromb Haemost 1993; 69: 177-194.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Sadler JE, Budde U, Eikenboom JCJ. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand factor. J Thromb Haemost 2006; 04: 2103-2114.
    CrossrefPubMedGoogle Scholar
  • 4 Sadler JE, Mannucci PM, Berntorp E. et al. Impact, diagnosis, and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-174.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 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.
    CrossrefPubMedGoogle Scholar
  • 6 Mannucci PM. Desmopressin in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
    PubMedGoogle Scholar
  • 7 Medical Product Safety.. In Healthy People 2010: A Systematic Approach to Health. Improvement 2003; 17: 3-19. Available at: http://www.healthypeople.gov. (Accessed February 13, 2012)
    PubMedGoogle Scholar
  • 8 Isaacs C, Roberts NH, Bailey FA. et al. Randomized placebo-controlled study or recombinant human interleukin-11 to prevent chaemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin. J Clin Oncol 1997; 15: 3368-3377.
    CrossrefPubMedGoogle Scholar
  • 9 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.
    CrossrefPubMedGoogle Scholar
  • 10 Ragni MV, Jankowitz RC, Jaworski K. et al. Phase II prospective open label trial of recombinant interleukin-11 (rhIL-11, Neumega®) in women with mild von Willebrand disease and refractory menorrhagia. Thromb Haemost 2011; 106: 641-645.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Haberichter SL, Merricks EP, Fahs SA. et al. Reestablishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 2005; 105: 145-152.
    CrossrefPubMedGoogle Scholar
  • 12 Benson RE, Catalfamo JL, Dodds WJ. A multispecies enzyme-linked immunosorbent assay for von Willebrand factor. J Lab Clin Med 1992; 119: 420-427.
    PubMedGoogle Scholar
  • 13 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.
    CrossrefPubMedGoogle Scholar
  • 14 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 haemophilia A. Blood 1993; 81: 2644-2651.
    PubMedGoogle Scholar
  • 15 Estey EH, Thall PF. New designs for phase 2 clinical trials. Blood 2003; 102: 442-448.
    CrossrefPubMedGoogle Scholar
  • 16 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. (Accessed February 13, 2012)
    PubMedGoogle Scholar
  • 17 Kaufmann JE, Vischer UM. Cellular mechanisms of the haemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 01: 682-689.
    CrossrefPubMedGoogle Scholar
  • 18 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-462.
    CrossrefPubMedGoogle Scholar
  • 19 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Olsen EHN, McCain AS, Merricks EP. et al. Comparative response of plasma VWF in dogs to upregulation of VWF mRNA by interleukin-11 versus Weibel-Palade body release by desmopressin (DDAVP). Blood 2003; 102: 436-441.
    CrossrefPubMedGoogle Scholar
  • 21 Denis CV, Kwack K, Saffaripour S. et al. Interleukin-11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models. Blood 2001; 97: 465-472.
    CrossrefPubMedGoogle Scholar
  • 22 Gordon MS, McCaskill-Steffens WJ, Battiato LA. et al. A phase I trial of recombinant human interleukin-11 (Neumega, rhIL-11®) in women with breast cancer receiving chaemotherapy. Blood 1996; 87: 3615-3624.
    PubMedGoogle Scholar
  • 23 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 chaemotherapy. Blood 1996; 87: 3607-3614.
    PubMedGoogle Scholar
  • 24 Ragni MV, Kessler CM. Haemophilia and von Willebrand Disease Subcommittee: Four Randomized Controlled Clinical Trial Concepts. State of the Science Symposium in Transfusion Medicine, Haemostasis and Thrombosis (SoSTMH), National Heart Blood Lung Institute, National Institutes of Health,; Bethesda MD,: September 14, 2009
    Google Scholar