Cardiac involvement remains the key prognostic factor in AL amyloidosis, but myocardium is part of an extensive vascular system covered by functionally active endothelium, critical for the homeostasis of circulation. Endothelial dysfunction may independently be involved in AL with prognostic implications. von Willebrand factor (vWF) is a large multimeric glycoprotein mainly produced (but not exclusively), stored and secreted by endothelial cells (ECs), participates in primary hemostasis, inflammation, and angiogenesis. Circulating vWF is a marker of EC activation and endothelial damage. We have previously shown that elevated levels of serum vWF antigen (vWF:Ag) are prognostic in AL amyloidosis, even among patients with advanced cardiac disease, but there is no validation in patients treated with contemporary regimens.

We measured vWF:Ag levels in 232 consecutive patients (pts) with newly diagnosed AL amyloidosis, treated in the Department of Clinical Therapeutics, Athens in serum collected before the initiation of therapy. The median age was 67 years; 56% were males; 84.5% had heart, 59% renal, 22% liver, 23% nerve and 28% soft tissue involvement. Per European Mayo 2004 stage distribution was 11%, 42%, 25% and 22% for stages 1, 2, 3A and 3B; 92% received bortezomib-containing (n=213) and 39% daratumumab-based primary therapy (n=91). The median serum level of vWF:Ag was 201 U/dL (range 70-1151). There was marginal association of vWF:Ag level with renal (p=0.05) and liver involvement (p=0.042) but no association with Mayo stage, heart, nerve or soft tissue involvement. vWF:Ag level was associated with D-dimer (r=0.345, p=0.001) and serum albumin (r=-0.289, p<0.001) levels and weak associations were noted with proteinuria (r=0.189, p=0.004), ALP (r=0.167, p=0.011) and systolic blood pressure (r=-0.189, p=0.004) but no correlation was found with cardiac biomarkers NTproBNP, hsTnT or GLS, eGFR or clonal markers (iFLC, BMPC infiltration). Median follow-up was 50 months and calculated median overall survival was 70 months. Mortality at 3- and 6-month was 14% and 19%, respectively. By ROC analysis the cutoff for vWF:Ag level associated with 3- and 6-month mortality was 210.5 U/dL and 208.5 U/dL, respectively, similar to the level of 230 IU/L identified in our previous study (Kastritis E et al Blood 2016). vWF:Ag levels ≥210 U/dL were associated with a 3-month mortality of 22% (vs 10% for vWF:Ag <210 U/dL, p=0.019) and 6-month mortality of 28% (vs 14%, p=0.014). vWF:Ag ≥210 U/dL identified pts with worse prognosis within Mayo stage 3 group (median OS 33.5 vs 7.3 months, p=0.040).

Then, we focused on pts who received daratumumab as first line therapy: pts with vWF:Ag ≥210 U/dL had 3-month mortality of 32% vs 13% for vWF:Ag <210 U/dL (p=0.032) and 6-month mortality of 42% vs 15% (p=0.004). Median OS for pts with vWF:Ag ≥210 U/dL was 31 months but was not reached for vWF:Ag <210U/dl (p=0.018). After adjustment for Mayo Stage, vWF:Ag ≥210 U/dL remained an independent predictor of inferior survival (HR 2.31, 95% CI 1.13-4.73, p=0.021). Among pts with Mayo stage 3, those with vWF:Ag ≥210 U/dL had significantly worse outcome (median OS 4 months vs not reached, p=0.008). Even after adjustment for European modification of Mayo Stage, vWF:Ag ≥210U/dL was an independent predictor of inferior survival (HR 2.11, 95% CI 1.03-4.30, p=0.040). In multivariate analysis that included the components of the European modification of Mayo stage and dFLC ≥180mg/L, vWF:Ag ≥210 U/dL (HR 2.26, 95% CI 1.08-4.71, p=0.030) and NTproBNP ≥8500 pg/mL were independently associated with inferior survival (HR 3.05, 95% CI 1.18-7.87, p=0.021). Endothelial dysfunction may also be related to renal dysfunction, and we evaluated renal outcomes among pts that received daratumumab. Pts with vWF:Ag ≥210 U/dl had a 2-year dialysis rate of 35% vs 6% and with risk of progression to dialysis (HR 7.44, 95% CI 1.34-41.34, p=0.022).

In conclusion, vWF:Ag levels remains a strong predictor of early mortality among patients treated with contemporary, including daratumumab-containing, therapies, independently of cardiac involvement. The current validation study places vWF:Ag as a promising, easy to measure biomarker that provides additional prognostic information and identifies patients at high risk of early death.

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2025
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