New and Emerging Targeted Therapies for Vascular Malformations

Table 1. Selected studies of sirolimus for vascular malformations
Authors	n	Dose	Target (ng/ml)	PJP prophylaxis	PJP	Neutropenia	Remarks
Prospective
Boscolo et al. [32]	6	2 mg/day	10–15	N	N	0	All adult
Adams et al. [46]	61	0.8 mg/m² q12h	10–15	Y	N	30	Blood/bone marrow toxicity
Hammer et al. [47]	19	0.8 mg/m² q12h	10–15	N	N	NI	Children
		2 mg/day	10–15	N	N	NI	Adults
Retrospective
Hammill et al. [33]	6	0.8 mg/m² q12h	10–15	Y	N	1	First retrospective series

NI not indicated, PJP pneumocystis jirovecii prophylaxis, q12h every 12 hours

Table 2. PJP infection related to treatment with mTOR inhibitors
Authors	Study type	Indication	n	n PJP	PJP prophylaxis	Monotherapy	Co-treatment	Target (ng/ml)
De Castro et al. [60]	Case control retrospective	Renal Tx	33	11	N	N	Antiproliferative drugs, CNI, CS
Saito et al. [61]	Case report	Renal cell Ca	1	1	N	Y	Previous sunitinib
Kuik et al. [62]	Case report	Metastatic breast Ca	1	1	N	N	Antitumoral drugs, hormonal treatment
Overwater et al. [63]	RCT cross over	TSC	23	0	N	Y	AED	5–10
Hu et al. [64]	Retrospective review	Heart Tx	38	6/13	Y 6 months	N	CS, tacrolimus, MMF	8–14
Krueger et al. [65]	Retrospective multicenter	TSC	45	0	N	Y	AED
Russel et al. [66]	Case report	KHE + KMP	1	1	N	N	Prednisolone, VCR	8–15
Ying et al. [67]	Case series	KHE + KMP	2	2	N	N	Methylprednisolone, propranolol
Li et al. [68]	Meta-analysis	TSC	671	0	?	Y	NI
Ghadimi et al. [69]	Meta-analysis	SOT	35,597	NI	Y	N	NI

AED anti-epileptic drugs, Ca carcinoma, CNI calcineurin inhibitor, CS corticosteroid, KHE Kaposiform hemangio-endothelioma, KMP Kassabach Merrit phenomenon, MMF mycophenolate mofetil, NI not indicated, PJP pneumocystis jirovecii prophylaxis, RCT randomized controlled trial, SOT solid organ transplantation, TSC tuberous sclerosis complex, Tx transplantation, VCR vincristine

Authors and Disclosures

An Van Damme^1,2, Emmanuel Seront^1,3, Valérie Dekeuleneer¹, Laurence M. Boon^1,4 and Miikka Vikkula^1,4,5

¹Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium miikka.vikkula@uclouvain.be
²Institut Roi Albert II, Department of Pediatric Hematology and Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
³Institut Roi Albert II, Department of Medical Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
⁴Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, 1200 Brussels, Belgium miikka.vikkula@uclouvain.be
⁵WELBIO (Walloon Excellence in Lifesciences and Biotechnology), de Duve Institute, University of Louvain, Brussels, Belgium miikka.vikkula@uclouvain.be

Author contributions
AVD performed the literature search and data analysis, and drafted the manuscript. ES, VD, LMB, and MV critically revised the work. The authors of this publication are members of the Vascular Anomalies Working Group (VASCA WG) of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), Project ID: 769036.

Conflict of interest
An Van Damme and Valérie Dekeuleneer have no conflicts of interest that are directly relevant to the content of this article. Emmanuel Seront discloses the following interactions with the medical industry: (1) clinical trial support for VASE: Pfizer [slow-flow vascular anomalies (rapamycin)] and (2) clinical trial support for TRAMAV: Novartis [fast-flow vascular anomalies (trametinib)]. Laurence M. Boon discloses the following interactions with the medical industry: (1) clinical trial support for VASE: Pfizer [slow-flow vascular anomalies (rapamycin)]; (2) clinical trial support for TRAMAV: Novartis [fast-flow vascular anomalies (trametinib)]; (3) clinical advisory board: Venthera [slow-flow malformations (transdermal PI3K inhibitor)]; and (4) clinical advisory board: Pierre Fabre [infantile hemangiomas (beta-blockers)]. Miikka Vikkula discloses the following interactions with the medical industry: (1) research grant from Deciphera Pharmaceuticals [venous malformations (rebastinib)] and (2) scientific and clinical advisory boards: Venthera [slow-flow malformations (transdermal PI3K inhibitor)].