Alveolar Hemorrhage Caused by the Combination of Immune Checkpoint Inhibitors (ICIs) and Angiogenesis Inhibitors: The Underlying Long-Term Vascular Endothelial Growth Factor (VEGF) Inhibition

Abstract

The combination of immune checkpoint inhibitors (ICIs) and other anticancer agents is the standard of care for various cancers. Bevacizumab, an anti-angiogenesis inhibitor, causes serious adverse events such as pulmonary hemorrhage (PH). Here, we present a case of drug-induced diffuse alveolar hemorrhage (DAH), an adverse event, in a patient with hepatocellular carcinoma who was treated with a combination of ICIs and anti-angiogenesis inhibitors after long-term use of lenvatinib, which inhibits vascular endothelial growth factor (VEGF). An 85-year-old man with hepatocellular carcinoma initially received lenvatinib, a multi-kinase inhibitor, but the drug was later switched to bevacizumab-atezolizumab combination therapy owing to disease progression. After five cycles, he developed dyspnea and diffuse ground-glass opacities, which improved with discontinuation of the combination therapy and initiation of steroid pulse therapy. Our case findings indicate that both ICIs and anti-angiogenesis inhibitors cause drug-induced DAH, and their combination may increase the severity of DAH. Moreover, long-term VEGF inhibition may induce the development of DAH. Clinicians need to be aware that long-term VEGF inhibition may be associated with DAH and should consider the risk management of such adverse events while using this combination therapy.

Keywords: adverse events; anti-angiogenesis inhibitor; combination therapy; diffuse alveolar hemorrhage; immune checkpoint inhibitor; long-term vegf inhibition.

Figure 1. Abdominal computed tomography findings

Abdominal computed tomography findings of hepatocellular carcinoma. An enlarged mass was then found in hepatic segment 8 (arrow).

Figure 2. Chest computed tomography findings on admission

Chest computed tomography revealed the presence of diffuse ground-glass opacities.

Figure 3. Image showing bronchoalveolar lavage (BAL)

Image showing bronchoalveolar lavage (BAL) performed via the right B3 segment; blood-stained lavage fluid was observed.

Figure 4. Cytological examination of the bronchoalveolar lavage fluid (BALF)

Cytological examination of the bronchoalveolar lavage fluid (BALF) using Papanicolaou-stained smears showing hemosiderin-laden macrophages.