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.

North American Study for the Treatment of Recurrent Epistaxis with Doxycycline: The NOSTRIL trial

“…Various antiangiogenic agents have been investigated as medical therapies in HHT, including bevacizumab, thalidomide, and pazopanib 2,5,23,24 . Intravenous bevacizumab, for example, has been shown to dramatically improve nosebleeds and reduce transfusion requirements via vascular endothelial growth factor inhibition 3,6,7 .…”

Systemic Antiangiogenic Therapies for Bleeding in Hereditary Hemorrhagic Telangiectasia: A Practical, Evidence-Based Guide for Clinicians

“…Although studies directly comparing antiangiogenics with surgical treatments do not exist, the accumulated evidence strongly argues that systemic targeted antiangiogenic therapy is the most effective treatment modality for achieving durable global hemostasis and normalization of hemostatic parameters in those patients with moderate-to-severe HHTassociated bleeding. [43][44][45] Due to their systemic nature, they frequently also cause fading and regression of telangiectasias at sites beyond the nasal cavity and GI tract, such as the skin, lips, and mouth, 46 and bevacizumab has also been evaluated for the treatment of high output cardiac failure in HHT through its therapeutic effect on diffuse liver AVMs. 47,48 While resolution of skin and oral telangiectasias is frequently welcomed by patients, this is largely cosmetic and systemic antiangiogenic therapy is not employed for this purpose in the absence of moderate-to-severe bleeding.…”

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies

“…18,19 Following promising results published in a small phase I study, 18 a recent observational study of 13 patients with severe HHT-associated bleeding and red cell transfusion-dependent anemia described striking hemostatic effectiveness of low-dose oral pazopanib in HHT. 19 All patients achieved transfusion independence, and most achieved a normal hemoglobin with minimal ongoing hematologic support requirements after pazopanib initiation. Doses between 25 and 300 mg daily were adequate to achieve these effects, with a median dose of 100 mg daily; for context, the starting dose of pazopanib in patients with cancer is 800 mg daily.…”

“…The most common adverse events seen with pazopanib in HHT are hypertension (~30%), lymphocytopenia (~25%), and fatigue (~25%), see Table 1. 19 Liver and thyroid function and the QTc interval must be monitored in patients receiving pazopanib. Figure 3 Advancements in the understanding of molecular signaling pathways contributing to the underlying pathophysiology of the complex vascular anomalies has led to the investigation of therapies targeting these pathways (Figure 5).…”

“…Because toxicity of pazopanib is clearly dose dependent, 29 significant toxicity with the modest doses used in HHT is unlikely. The most common adverse events seen with pazopanib in HHT are hypertension (~30%), lymphocytopenia (~25%), and fatigue (~25%), see Table 1 19 . Liver and thyroid function and the QTc interval must be monitored in patients receiving pazopanib.…”