Abstract

Von Willebrand disease (VWD) is the single most common congenital bleeding disorder, and among women, menorrhagia is the most common bleeding symptom. Although DDAVP is the treatment of choice for those with type 1 VWD, its use may be limited by tachyphylaxis, allergic reactions, or unresponsiveness. We previously showed that recombinant human IL-11 (rhIL-11, Neumega), a gp-130 signaling cytokine with hematopoietic and anti-inflammatory activity, increases VWF levels 2–3 fold when given subcutaneously daily in individuals with mild VWD, and is well tolerated. We, therefore, initiated a Phase II clinical trial to determine the efficacy and safety of rhIL-11 in women with VWD and refractory menorrhagia, despite estrogen, DDAVP, and/or other treatment. We report the results of the first four subjects, age 28–40, with VWF:RCo 0.22–0.37 U/ml at diagnosis, normal VWF multimers, and bleeding severity scores (BSS) 4–6. rhIL-11 was given in a daily subcutaneous dose of 25 mcg/kg for 4 days, followed by monthly home self-injection for up to 7 days during each of six consecutive menstrual cycles, beginning on the first day of each cycle. Menstrual bleeding severity was measured by

  1. a validated bleeding pictorial assessment chart (BPAC) (Janssen, Obstet Gynecol, 1995) and

  2. cycle severity rating (CSR), as compared with two pre-treatment baseline menstrual cycles. BPAC scores were compared with standardized cutoff score for menorrhagia of 185.

Cycle severity ratings (CSR) were rated on a nominal scale, with 0=mild bleeding; 1=moderate bleeding, less than usual cycle; 2= moderately severe bleeding, not as severe as worst cycle; and 3=severe bleeding, as severe as worst cycle. The drug was well tolerated with less than grade 1 toxicity, including mild conjunctival erythema and mild fluid retention (fingers) in one each. Following treatment with rhIL-11, there was a significant reduction in BPAC and cycle severity rating during the seven days the drug was given, as compared with the first seven days in cycles prior to rhIL-11 (see Table). Cycle length also shortened, but this did not reach significance. These was an associated increase in VWF:RCo, VWF:Ag, and FVIII:C on day 4 of rhIL-11 dosing, as compared with pre-rhIL-11 levels day 1. These data suggest that rhIL-11 improves hemostasis and reduces bleeding severity when used during the first seven days of menses in women with VWD. Further studies are needed to confirm these findings.

Mensural Cycle Bleeding Severity in Women with VWD With and Without rhIL-11

No. CyclesBleeding Pictorial Chart (BPAC) No. >185Cycle Severity Rating (CSR)Cycle Length (Day)VWF:Rco U/mlVWF:Ag U/mlFVIII:C U/ml
Significance, *p<0.05; †p<0.01; ‡p=0.014 
CYCLES WITHOUT rhIL-11 6/7 (85.7%) 2.0±5 12±5 0.92±0.13 1.16 ± 0.06 0.60±0.09 
CYCLES WITH rhIL-11 15 4/15 (23.5) ‡ 1.1±0.2† 7±1 1.71±0.17† 1.70±0.17† 1.02 ± 0.12* 
No. CyclesBleeding Pictorial Chart (BPAC) No. >185Cycle Severity Rating (CSR)Cycle Length (Day)VWF:Rco U/mlVWF:Ag U/mlFVIII:C U/ml
Significance, *p<0.05; †p<0.01; ‡p=0.014 
CYCLES WITHOUT rhIL-11 6/7 (85.7%) 2.0±5 12±5 0.92±0.13 1.16 ± 0.06 0.60±0.09 
CYCLES WITH rhIL-11 15 4/15 (23.5) ‡ 1.1±0.2† 7±1 1.71±0.17† 1.70±0.17† 1.02 ± 0.12* 

Disclosures: Ragni:Wyeth Pharmaceuticals: Research Funding, Supplied drug for research; Baxter Bioscience: Research Funding; Chiron Corporation: Research Funding; Manchester Hospital NHS Trust: Research Funding; Archemix Corporation: Consultancy, Research Funding; Bayer : Consultancy, Research Funding; Novo-Nordisk: Consultancy, Research Funding. Off Label Use: Off-label use of recombinant interleukin-11 (Neumega) in von Willebrand disease.

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