Aflibercept-mediated early angiogenic changes in aggressive B-cell lymphoma

Diffuse large B-cell lymphoma is the most common and one of the most aggressive lymphomas in adults. The standard, R-CHOP-based treatment needs improvement. There has been recent interest in anti-angiogenic therapy, but its cellular effects in lymphoma are little known.

In five aggressive B-cell lymphoma patients, we analyzed the microvessel and lymphoma cell changes after Aflibercept, an angiogenic inhibitor. Under ultrasonography, we performed two biopsies, one before any treatment and one two hours after Aflibercept, before R-CHOP. Using ultrasonography, immuno-histochemistry, double immuno-fluorescent staining, and electron microscopy, we compared the early changes induced by Aflibercept to the early changes induced by R-CHOP in three control patients.

We identified microvessel damage in the five patients treated with Aflibercept but not in the three patients treated with R-CHOP. Two hours after Aflibercept, microvessel damage was focal, with severely damaged microvessel sections close to normal ones in the same area; different stages of microvessel damage were concomitantly found, with an increase in relative necrosis area in three cases. There was no difference in necrosis or relative microvessel area after R-CHOP. For lymphoma cells, the two biotherapies induced similar changes, with increase in apoptosis but not in proliferation.

We identified focal microvascular damage, necrosis, and apoptosis of lymphoma cells in aggressive B-cell lymphoma as soon as 2 h after Aflibercept. This suggests that there is more than one mechanism associated with the early effect of anti-angiogenic therapy in lymphoma.