A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease.
von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF(+/-) mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 mug kg(-1) subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 mug kg(-1), on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.
Ragni
M V
MV
Department of Medicine/Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ragni@dom.pitt.edu
Jankowitz
R C
RC
Chapman
H L
HL
Merricks
E P
EP
Kloos
M T
MT
Dillow
A M
AM
Nichols
T C
TC
D000328:Adult; D003894:Deamino Arginine Vasopressin / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D006490:Hemostatics / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007279:Injections, Subcutaneous; D017370:Interleukin-11 / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D010976:Platelet Count; D016133:Polymerase Chain Reaction / Q000379:methods; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D055815:Young Adult; D014842:von Willebrand Diseases / Q000097:blood / Q000188:drug therapy*; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D006490:Hemostatics; D017370:Interleukin-11; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin