Acquired von Willebrand syndrome associated with monoclonal gammopathy of undetermined significance – successful treatment with lenalidomide and dexamethasone

Objective Management of hemorrhagic complications in acquired von Willebrand syndrome (AVWS) can be challenging. This is particularly true for gastrointestinal (GI) bleeding from AVWS-associated angiodysplasia. In AVWS, secondary to monoclonal gammopathy of undetermined significance (MGUS), therapy with immunomodulatory drugs such as thalidomide or lenalidomide in combination with dexamethasone has been proposed, although not evidence-based. Here, we assessed the effect of this regimen in patients, who failed to respond to intravenous immunoglobulin treatment (IVIG) in a sustained effect.

Material and Methods We report on two males (aged 45 and 54 years) with MGUS-associated AVWS suffering from severe, life-threatening GI and mucocutaneous bleeding. Multimer (MM) analysis of the von Willebrand factor (VWF) displayed loss of large MM, confirming AVWS. Both patients gave informed consent after careful information about off-label use of lenalidomide and the benefit-risk assessment.

Results Patient 1 had experienced recurrent GI bleeding due to angiodysplasia. Over a 12-month period, no remission was achieved by high-dose IVIG treatment (1g/kg/d for 2 days). Therapy with lenalidomide in 28-days-cycles (21 days of treatment, followed by 7 days of pause) was started at low dose (5 mg once daily) due to elevated liver enzymes and combined with weekly administration of dexamethasone (40 mg). Upon stepwise dose increase of lenalidomide (up to 25 mg once daily), bleeding resolved without continued IVIG. During a 2-year follow-up until today, hemorrhage did not recur and VWF parameters restored completely (Table 1). Patient 2 suffered from recurrent spontaneous hemorrhage including severe thoracic hematoma while on IVIG treatment. Upon administration of lenalidomide (20mg once daily) plus dexamethasone (40 mg once weekly) in 28-days cycles, the patient experienced complete remission with regard to any new bleeding episodes and VWF abnormalities during a 2-year follow-up until today (Table 1).

Conclusion Our observations confirm that combined treatment with lenalidomide and dexamethasone can increase VWF plasma levels and resolve bleeding in MGUS-associated AVWS. The findings are compatible with the hypothesis that this effect results from lenalidomide-mediated inhibition of otherwise increased clearance and degradation of VWF in MGUS, as suggested by others.

Tab 1. Course of laboratory parameters in acquired von Willebrand syndrome associated with monoclonal gammopathy of undetermined significance at time of diagnosis, prior to therapy with immunomodulatory agents (initiated 3-4 weeks after short-lasting response of IVIG treatment) and current outcome after two years of combined treatment with lenalidomide and dexamethasone. Abbreviations: ADP, adenosine diphosphate; APTT, activated partial thromboplastin time; FVIIIc, chromogenic factor VIII activity; PFA, platelet function analyzer; VWF, von Willebrand factor; sec, seconds

Publication History

Article published online:
18 June 2021