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Successful treatment of acquired von Willebrand disease with lenalidomide leading to dramatic resolution of intractable gastrointestinal bleeding: A case report

Acquired von Willebrand disease (AVWD) has a variety of causes including monoclonal gammopathy of uncertain significance (MGUS). We report the case of a patient with AVWD secondary to IgM MGUS who had intractable gastrointestinal (GI) bleeding that failed to respond to multiple lines of therapy but finally with lenalidomide has led to a dramatic reduction of the bleeding symptoms. A 73yearold man was referred to our haemophilia centre with a 2to 3year history of prolonged bleeding after cuts, 2 episodes of epistaxis requiring either cautery or nasal packing and GI bleeding with dark stools. He had 45 units of transfused packed red cells over the 3 years prior to presentation at our haemophilia centre. He reported no abnormal bleeding prior to the previous 3 years and previously had a malignant polyp removed from his bowel, a transurethral resection of the prostate and pleurodesis for a chronic rightsided pneumothorax due to a scuba diving injury without bleeding complications. He had a past medical history of hypertension and diabetes mellitus. At presentation, medications were ferrous sulphate, metformin, ramipril and simvastatin. He had no family history of bleeding. Laboratory investigations revealed von Willebrand Factor (VWF) antigen 0.31 (0.531.49 U/mL), VWF ristocetin cofactor assay 0.13 (0.411.27 U/ mL) and 1 stage factor VIII assay 0.43 (0.571.41 IU/mL). Extensive workup for other coagulation abnormalities including factor XIII, XI, IX, X, VII, V, II, fibrinogen, impedance platelet aggregometry and platelet nucleotides were normal. Liver, renal and bone profile were normal. Serum electrophoresis revealed a IgM paraprotein which was too low for quantification (<2 g/L). A bone marrow aspirate and trephine biopsy, performed without any bleeding complications, showed some nondiagnostic dyserythropoiesis and 8% lymphocytes with normal immunophenotype. A CT neck, chest, abdomen and pelvis revealed no evidence of lymphoma or lytic lesions. A transthoracic echocardiogram revealed no valvular abnormalities. A diagnosis of AVWD secondary to an IgM MGUS was established. Multiple endoscopic examinations of the GI tract, including upper and lower endoscopy and capsule endoscopy, revealed multiple bleeding points in the duodenum and jejunum without a specific lesion. Upper GI histopathology (random biopsies) was normal. A 2week course of tranexamic acid failed to control the GI bleeding so Wilate (human plasma derived WF and factor VIII concentrate; Octapharma, NJ, USA) prophylxais was added at a dose of 23 IU/kg VWF:RCo twice per week with trough VWF ristocetin cofactor assay levels of 0.120.20 U/mL (0.411.27 U/mL) with normal VWF antigen and factor VIII levels (treatment and bleeding course summarized in Figure 1). Wilate dose was escalated to 34 IU/kg VWF:RCo twice daily with failure to control the GI bleeding and trough VWF ristocetin cofactor assay levels of 0.330.40 U/mL (0.411.27 U/mL). After 8 months of Wilate prophylaxis, a course of plasma exchange was given without improvement in either VWF levels, GI bleeding or transfusion requirements. After 9 months, 2 g/kg intravenous immunoglobulin was administered again with failure to control bleeding, transfusion requirement or VWF levels. Atorvastatin 20 mg once daily was added and octreotide 100 μg subcutaneously twice daily. Ten months after presentation, 6 cycles of rituximab and bendamustine were administered on 28day cycles (rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 and 2). After 5 cycles of chemotherapy, the paraprotein became undetectable but the GI bleeding continued unabated. The patient was switched to Voncento 30 IU/kg VWF:RCo (human plasma derived WF and factor VIII concentrate; CSL Behring, PA, USA) twice daily empirically to investigate whether a product switch may help control bleeding. Trough ristocetin cofactor assay levels were measured in the normal range at times but on other occasions as low as 0.12 U/mL (0.411.27 U/mL) with normal VWF antigen and factor VIII levels but bleeding continued, despite the undetectable paraprotein. In view of the intractable bleeding in February 2017, the patient was commenced on lenalidomide 25 mg once daily for 21 days followed by a rest week, in repeated 28day cycles. Transfusion dependency decreased on a monthly basis until June 2017 and July 2017 when no red cell units had been transfused. This was the first 2month period that he has had without transfusion as he came under the care of our haemophilia centre (Figure 1). In August 2017, he had a 1week delay in lenalidomide restarting due to therapy related neutropenia and 2 units of blood were transfused during the subsequent delay in restarting lenalidomide. In view of cytopenias, the dose was reduced to 15 mg daily for 21 days followed by a rest week. In November 2017, the patient experienced further melaena and required 8 units of blood that month; the dose was increased to 20 mg once daily and no further bleeding has occurred since (as of January 2018). The Voncento had been tapered down to 28 IU/kg VWF:RCo alternate days, and he had taken this since July 2017; it was therefore increased in November 2017 to once daily. The patient is currently receiving Voncento 28 IU/ kg VWF:RCo daily with trough levels of VWF antigen and ristocetin cofactor assay levels within the normal range for our laboratory. The paraprotein is undetectable on lenalidomide treatment. To the best of our knowledge, this is the third case report of AVWD reported in the literature that has been treated with lenalidomide. In the Accepted: 3 February 2018