Emerging role of bevacizumab in management of patients with symptomatic hepatic involvement in Hereditary Hemorrhagic Telangiectasia
Authors: Ajay Chavan, Silke Schumann‐Binarsch, Bernhard Schmuck, Franziska Oltmer, Urban Geisthoff, Florian Hoppe, Kornelia Wirsching, Juergen Klempnauer, Michael Manns, Rohit Philip Thomas, Claus‐Henning Köhne
Journal: American Journal of Hematology (2017)

In Hereditary Hemorrhagic Telengiectasia (HHT) patients with symptomatic hepatic involvement requiring invasive treatment, hepatic artery embolization (HAE) and liver transplantation (LT) are not without morbidity and mortality.1-3 This makes a less invasive alternative attractive. In our study we hypothesize that systemic bevacizumab therapy alleviates liver related pain and cardiac overload thus obviating the need for HAE or LT. Between October 2010 and April 2016, we prospectively treated 21 such patients systemically with the vascular endothelial growth factor (VEGF)-inhibitor bevacizumab (5 mg/kg/dose, 6 doses administered every two weeks). The entire therapy was repeated at follow-up if symptoms causing significant clinical impairment recurred. Clearance was obtained from the ethical committee regarding off-label use of bevacizumab in nononcologic patients. Full informed consent was obtained from all patients. The inclusion criterion was all HHT patients with symptomatic hepatic involvement requiring invasive therapy. Asymptomatic patients with hepatic involvement, patients without hepatic involvement and those who had undergone previous liver transplantation were excluded from the cohort. The primary end point was to determine the changes in the grade of abdominal pain (capsular pain, ischemic cholangiopathy, abdominal angina), cardiac output and the New York Heart Association (NYHA) stage in HHT patients with hepatic involvement before and three months after systemic bevacizumab therapy. The secondary end points included the epistaxis response to therapy, the change in hemoglobin after therapy, the necessity for repeat therapies, and the safety and tolerability of bevacizumab. Demographic and clinical data as well as other relevant variables collected for all subjects included age, gender, blood pressure readings, echocardiographically determined cardiac output, the New York Heart Association (NYHA) stage, routine blood and urine parameters (including hemoglobin and serum creatinine), epistaxis grade according to the National Cancer Institute´s common toxicity criteria scale and the pain grade according to the Numerical Rating Scale (NRS) (grade 0 denoting "no pain" and grade 10 the "worst imaginable pain") (Table 1). Adverse events related to medication use (hypertension, proteinuria, thromboembolic episodes, bleeding episodes or any other grade III-V events) were specifically sought for and recorded during and after bevacizumab therapy. The median patient age was 58 years (range 42–71 years) and median follow-up was 33 months (range 3–70 months). Repeat therapies (1 to 4) were necessary in nine patients. Insufficient clinical improvement post-therapy necessitated HAE in three patients. Two stabilized thereafter and required no further therapy. The third patient required additional liver transplantation. No arterial embolic episodes in the systemic circulation or proteinuria were noted. Adverse events (AE) included grade I hypertension (4 patients), grade I epistaxis (1 patient), grade I hematemesis (1 patient), grade III hematemesis (1 patient) and grade IV pulmonary embolism (1 patient). Abdominal pain was a presenting symptom in 15 patients. The NRS grades pretherapy and post-therapy were 2–7 and 0–3 respectively. Mean pain grade improved from 3·0 ± 2·2 (95% CI 1·99–3·91) pretherapy to 0·9 ± 1·0 post-therapy (95% CI 0·48–1·33) (P < .001) (Table 1) (Supporting Information Figure S1). Cardiac output pretherapy ranged between 4·9 L/min and 19 L/min (mean 8·7 L/min ± 3·5) (95% CI 7·25–10·24). Following therapy, the mean value fell significantly to 6·5 L/Min ± 1·8 (95% CI 5·73–7·24) (range 4·3 L/min-10·0 L/min) (P < .0008) (Table 1) (Supporting Information Figure S2). The fall in cardiac output was associated with an improvement in the signs and symptoms of cardiac decompensation as signified by the mean NYHA stage improving from 2·8 ± 0·7 (95% CI 2·49–3·13) pretherapy to 1·6 ± 0·9 (95% CI 1·25–1·99) (P < .0001) (Table 1) (Supporting Information Figure S3) following therapy. Nasal bleeding in varying degrees was present in all but one patient. One patient each had grade 0 and grade 1 epistaxis, eight patients grade 2 and 11 patients grade 3 epistaxis. Following therapy, nasal bleeding subsided to grade 0–1 in all patients. The mean epistaxis grade fell significantly from 2·4 ± 0·8 (95% CI 2·04–2·73) to 0·9 ± 0·4 (95% CI 0·70–1·01) (P < .0001) (Table 1) (Supporting Information Figure S4). The mean hemoglobin levels improved from 10·8 g/dl ± 2·6 (95% CI 9·70–11·93) to 12·4 g/dl ± 1·7 (95% CI 11·66–13·13) (P < .0002) (Table 1) (Supporting Information Figure S5). Our results demonstrate that abdominal pain as well as cardiac overload in HHT patients with severe hepatic involvement respond well to bevacizumab. Clinically, our patients reported a marked improvement of pain, exertional dyspnea, early fatigability and general performance. Similar results were reported by Dupuis-Girod in 2012, however in a cohort less advanced in their disease.4 An additional benefit of systemic bevacizumab is the favorable response to therapy of epistaxis and hemoglobin as reported by other authors as well.5, 6 It is worthy of mention however, that clinical symptoms recur gradually at varying intervals between five and 26 months thus making repeat therapies necessary. Furthermore, ancillary procedures such as HAE or LT may be required in patients with insufficient clinical improvement, as experienced in three of our patients. All three patients presented with advanced cardiac disease in NYHA stage 3 suggesting that advanced disease may adversely influence adequate response to bevacizumab. This may make a case for instituting bevacizumab therapy earlier on in the course of the disease. Clinical improvement without significant toxicity (maximum grade I) was noted in 18 patients. One nonresponder tolerated therapy without any AE. In the remaining two patients, we experienced one grade III and one grade IV AE each, of whom the patient with the grade III hematemesis had similar episodes of hematemesis prior to bevacizumab as well. As opposed to our results, neither thromboembolic complications nor hemorrhage were reported by Dupuis-Girod and colleagues.4 In their cohort however, patients with previous history of thrombosis, atrial fibrillation, thrombopenia and those on anticoagulant therapy had been excluded from the study population.4 This was not so in our cohort. The low AE rate despite this, further strengthens the case for bevacizumab therapy prior to invasive measures such as HAE or LT. Further studies with larger patient numbers and longer follow-up in HHT patients with severe hepatic involvement are warranted to confirm our findings and to clearly establish the role of bevacizumab in the treatment algorithm of such patients. We are especially grateful to Mrs. Kerstin Büschen for her able assistance in co-ordinating patient therapies and collecting clinical data and to Miss Lilia Kruse for her assistance with the statistical analysis. The study was partly funded by the German Hereditary Hemorrhagic Telangiectasia (HHT) foundation (Morbus Osler-Stiftung, www.morbus-osler.de). There are no financial, personal or academic conflicts of interest, with respect to any of the authors. Ajay Chavan http://orcid.org/0000-0002-9541-9407 Additional Supporting Information may be found in the online version of this article at the publisher's website. Supporting Information Figure-1 Supporting Information Figure-2 Supporting Information Figure-3 Supporting Information Figure-4 Supporting Information Figure-5 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.