Systemic bevacizumab to facilitate anticoagulation in antiphospholipid syndrome and bleeding gastrointestinal angiodysplasia

Journal of Thrombosis and Thrombolysis - Bleeding gastrointestinal angiodysplasia may occur in patients with vasculitis and can be challenging to treat. We describe the novel use of bevacizumab...     

A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumor s and hematologic malignancies

Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy treatment delays, dose reductions, and discontinuation. There is no US Food and Drug Administration (FDA)-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at four US centers. The primary outcome was achievement of a romiplostim response (median on-romiplostim platelet count ≥75x10⁹/L and ≥30x10⁹/L above baseline). Secondary outcomes included time to platelet count ≥100x10⁹/L and rates of the following: platelet count <100×10⁹/L, platelet count <75x10⁹/L, platelet count <50x10⁹/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. A total of 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of four (range: 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays, and 89% avoided platelet transfusions. Median per-patient platelet count on romiplostim was significantly higher than baseline (116x10⁹/L vs. 60x10⁹/L; P<0.001). Bone marrow (BM) tumor invasion, prior pelvic irradiation, and prior temozolomide exposure predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays/bleeding; intracycle dosing had an incidence rate ratio (IRR) for dose reduction/treatment delay of 3.00 (95%CI: 1.30-6.91; P=0.010) and an IRR for bleeding of 4.84 (95%CI: 1.18-19.89, P=0.029) compared with weekly dosing. Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with BM involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.     

Systemic bevacizumab as salvage therapy for persistent severe bleeding and anemia in heyde syndrome following aortic valve replacement

Journal of Thrombosis and Thrombolysis - Heyde syndrome is characterized by the co-occurrence of aortic stenosis and bleeding gastrointestinal angiodysplasias, often with acquired von Willebrand...     

An international,multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder that causes chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHTassociated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, Epistaxis Severity Score (ESS), red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. Bevacizumab was given to 238 HHT patients for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% confidence interval: 2.9-3.5 g/dL); i.e., from a mean hemoglobin of 8.6 (8.5-8.8) g/dL to 11.8 (11.5-12.1) g/dL; P<0.0001) and decreased the ESS by 3.4 (3.2-3.7) points (mean ESS 6.8 [6.6-7.1] versus 3.4 [3.2-3.7]; P<0.0001) during the first year of treatment. Compared with 6 months before treatment, the number of red blood cell units transfused decreased by 82% (median of 6.0 [interquartile range, 0.0-13.0] units versus 0 [0.0-1.0] units; P<0.0001) and iron infusions decreased by 70% (median of 6.0 [1.0-18.0] infusions versus 1.0 [0.0-4.0] infusions, P<0.0001) during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of the underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as-needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective for managing chronic bleeding and anemia in HHT.     

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

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.