Veroniek E M Harbers1,2, Gerard A P J M Rongen3, Carine J M van der Vleuten4,5, Bas H Verhoeven6,5, Peter C J de Laat7, Chantal M A M van der Horst8, Willemijn M Klein5,9, Leo J Schultze Kool10,5, D Maroeska W M Te Loo5,11. 1. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 22, 6525 GA, Nijmegen, Gelderland, the Netherlands. veroniek.harbers@radboudumc.nl. 2. HECOVAN Workgroup, Nijmegen, the Netherlands. veroniek.harbers@radboudumc.nl. 3. Department of Internal Medicine and Pharmacology-Toxicology, Radboud University Medical Center, Geert Grooteplein Noord 21, 6525 EZ, Nijmegen, Gelderland, the Netherlands. 4. Department of Dermatology, Radboud University Medical Center, Rene Descartesdreef 1, 6525 GL, Nijmegen, Gelderland, the Netherlands. 5. HECOVAN Workgroup, Nijmegen, the Netherlands. 6. Department of Surgery, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, Gelderland, the Netherlands. 7. Department of Pediatric Oncology, WEVAR-Team, Rotterdam Erasmus MC-Sophia, Postbus 2040, 3000 CA, Rotterdam, Zuid-Holland, the Netherlands. 8. Department of Plastic Reconstructive and Hand Surgery, AVA-Team, Amsterdam University Medical Center, Noord-Holland, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. 9. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, Gelderland, the Netherlands. 10. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 22, 6525 GA, Nijmegen, Gelderland, the Netherlands. 11. Department of Pediatric Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, Gelderland, the Netherlands.
Abstract
INTRODUCTION: Patients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10-15 ng/ml were well tolerated; however, in a relative high percentage of patients sirolimus caused serious adverse events (AEs). METHODS: A case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4-10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading. RESULTS: An improvement in symptoms was seen in 92% (n = 11/12) of patients. In nine patients pain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus. CONCLUSIONS: Low dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition.
INTRODUCTION:Patients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10-15 ng/ml were well tolerated; however, in a relative high percentage of patientssirolimus caused serious adverse events (AEs). METHODS: A case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4-10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading. RESULTS: An improvement in symptoms was seen in 92% (n = 11/12) of patients. In nine patientspain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus. CONCLUSIONS: Low dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition.
Authors: Lee S Nguyen; Mathieu Vautier; Yves Allenbach; Noel Zahr; Olivier Benveniste; Christian Funck-Brentano; Joe-Elie Salem Journal: Drug Saf Date: 2019-07 Impact factor: 5.606
Authors: Veroniek E M Harbers; Nathalie van der Salm; Sjoert A H Pegge; Carine J M van der Vleuten; Bas H Verhoeven; Sabine L A G Vrancken; Leo J Schultze Kool; Joris Fuijkschot; D Maroeska M W M Te Loo Journal: Br J Clin Pharmacol Date: 2022-01-18 Impact factor: 3.716