Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia

Abstract

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.

Keywords: Anemia; Angiogenesis; Bleeding; Epistaxis; Gastrointestinal bleeding; HHT; Hereditary hemorrhagic telangiectasia; Iron deficiency; Osler-Weber-Rendu; Pazopanib.

Fig. 1

Predefined pazopanib treatment pathway. Patients had required in-person clinic visits at least every 3 months and either telephone or in-person visits monthly (for drug titration and TEAE assessment). RBC red blood cell, CBC complete blood count, TSH thyroid-stimulating hormone, ESS epistaxis severity score, ECG electrocardiogram, TEAE treatment-emergent adverse event

Fig. 2

Flow diagram describing patient inclusion and exclusion in study analysis

Fig. 3

Box-and-whisker plots (box represents median and interquartile range and tails represent minimum and maximum) showing effect of pazopanib on hematologic parameters and epistaxis severity. A Hemoglobin, B Epistaxis severity score, C RBC transfusion, D Iron infusion, E Serum ferritin, F Transferrin saturation. Mo months, PreTx pretreatment, On Tx on-treatment

Fig. 4

Swimmer plot detailing timeline of red cell transfusion and iron infusion events for each patient during the 24 months prior to pazopanib initiation and 36 weeks following its initiation