Acute Immune-Mediated Thrombocytopenia due to Oxaliplatin and Irinotecan Therapy.

We describe a case of a 63-year-old woman with advanced colon cancer and liver metastases who was treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and cetuximab chemotherapy. She tolerated 13 cycles of chemotherapy without any significant hematological side effects, but after the 14th cycle, she developed melena and was admitted for severe thrombocytopenia. After supportive care, the platelet counts rapidly improved to 76,000/µL. Upon initiation of FOLFIRI and cetuximab chemotherapy, she again developed rectal bleeding and severe thrombocytopenia with a platelet count of 6000/µL. Lab testing was positive for oxaliplatin and irinotecan drug-dependent platelet antibodies on flow cytometry assay. Drug-induced thrombocytopenia (DITP) is associated with several classes of drugs with several proposed underlying mechanisms. Prospective studies are needed to further address different mechanisms of drug-induced thrombocytopenia.

Aflibercept exerts antivascular effects and enhances levels of anthracycline chemotherapy in vivo in human acute myeloid leukemia models.

We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients.