pazopanib and Epistaxis

As precision medicine has become a focus in oncology in recent years, many targeted and biologic agents are being used along with or in place of traditional cytotoxic chemotherapy. As these drugs have been developed and some have received FDA approval, we have gained substantial data about the adverse event profiles. However, the management and approach to the toxicities incurred and subsequent complications are often not well understood, especially for physicians who have a varied clinical practice. The purpose of this review is to provide an overview of the frequency and types of adverse events and appropriate management steps when prescribing modern targeted therapies for gynecologic cancers in the classes of anti-angiogenic agents, poly-ADP-ribose polymerase (PARP) inhibitors, and immunotherapy drugs.

Topics: Anemia; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Autoimmune Diseases; Bevacizumab; Diarrhea; Epistaxis; Fatigue; Female; Genital Neoplasms, Female; Headache; Hemorrhage; Humans; Hypertension; Indazoles; Intestinal Perforation; Molecular Targeted Therapy; Nausea; Neutropenia; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Proteinuria; Pyrimidines; Risk Assessment; Sulfonamides; Vomiting; Water-Electrolyte Imbalance

Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treated on a predefined institutional pazopanib treatment pathway (with data collected retrospectively). The primary endpoint was achievement of transfusion independence. Secondary endpoints included hemoglobin, epistaxis severity score, RBC transfusion and iron infusion requirements, number of local hemostatic procedures, ferritin and transferrin saturation, compared using paired and repeated measures mean tests. Thirteen transfusion-dependent HHT patients received pazopanib [median (range) dose 150 (25-300) mg daily)] for a median of 22 months. All patients achieved transfusion independence. Compared with pretreatment, pazopanib increased mean hemoglobin by 4.8 (95% CI, 3.6-5.9) g/dL (7.8 vs. 12.7 g/dL, P < 0.0001) and decreased mean epistaxis severity score by 4.77 (3.11-6.44) points (7.20 vs. 2.43 points, P < 0.0001) after 12 months of treatment. Compared with 3 months of pretreatment, RBC transfusions decreased by 93% (median of 16.0 vs. 0.0 units, P < 0.0001) and elemental iron infusion decreased by 92% (median of 4500 vs. 0 mg, P = 0.005) during the first 3 months of treatment; improvements were maintained over time. Pazopanib was well-tolerated: hypertension, lymphocytopenia, and fatigue were the most common TEAEs. In conclusion, pazopanib was safe and effective to manage severe bleeding in HHT, liberating all patients from transfusion dependence and normalizing hematologic parameters at doses lower than used to treat malignancies. These findings require confirmation in a randomized trial.

Topics: Anemia; Epistaxis; Humans; Indazoles; Pyrimidines; Retrospective Studies; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic

Hereditary hemorrhagic telangiectasia (HHT) most commonly manifests with nasal mucosal telangiectasias, and vascular endothelial growth factor (VEGF) plays a significant role in this angiodysplasia. We describe a patient with HHT with epistaxis recalcitrant to several endonasal procedures and six cycles of intravenous bevacizumab, for which he was dependent on iron infusions and packed red blood cells transfusions. He then started pazopanib at 100 mg with dramatic improvements in epistaxis and normalization of hemoglobin and iron levels, without replenishment needs for 12 months. This is the first report on the efficacy of pazopanib with high selectivity for abrogating VEGF receptor-2 signaling in HHT, and needs to be explored further. Laryngoscope, 128:2234-2236, 2018.

Topics: Anemia, Iron-Deficiency; Angiogenesis Inhibitors; Bevacizumab; Epistaxis; Erythrocyte Transfusion; Hemoglobins; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic