New and Emerging Targeted Therapies for Vascular Malformations

Abstract and Introduction

Abstract

Vascular malformations are inborn errors of vascular morphogenesis and consist of localized networks of abnormal blood and/or lymphatic vessels with weak endothelial cell proliferation. They have historically been managed by surgery and sclerotherapy. Extensive insight into the genetic origin and molecular mechanism of development has been accumulated over the last 20 years. Since the discovery of the first somatic mutations in a vascular anomaly 10 years ago, it is now recognized that they are perhaps all caused by inherited or somatic mutations in genes that hyperactivate two major intracellular signaling pathways: the RAS/MAPK/ERK and/or the phosphatidylinositol 3 kinase (PIK3)/protein kinase B/mammalian target of rapamycin (mTOR) pathway. Several targeted molecular inhibitors of these pathways have been developed, mostly for the treatment of cancers that harbor mutations in the same pathways. The mTOR inhibitor sirolimus is the most studied compound for the treatment of venous, lymphatic, and complex malformations. Disease responses of vascular malformations to sirolimus have now been reported in several studies in terms of clinical changes, quality of life, functional and radiological outcomes, and safety. Other targeted treatment strategies, such as the PIK3CA inhibitor alpelisib for PIK3CA-mutated vascular malformations, are also emerging. Repurposing of cancer drugs has become a major focus in this rapidly evolving field.

Introduction

Vascular anomalies are a heterogeneous group of disorders characterized by abnormal growth and/or development of lymphatic and/or blood vessels. They remain a diagnostic and therapeutic challenge and are associated with very diverse symptomatology and morphology. Diagnostic and therapeutic progress for these disorders has been greatly facilitated by the classification and terminology initiated by Mulliken and Glowacki.^[1] The International Society for the Study of Vascular Anomalies has updated and extended this classification since 1996 and published the current extended version in 2015.^[2] The classification was further updated in 2018 to include the most current information and is published on the International Society for the Study of Vascular Anomalies website (https://www.issva.org).^[3]

The basis of this classification is the division of vascular anomalies into vascular tumors and vascular malformations. Vascular tumors are characterized by the abnormal proliferation of endothelial cells and blood vessels. They are subclassified as benign, locally aggressive, borderline, and malignant tumors.^[2] Vascular malformations are inborn errors of vascular morphogenesis and consist of networks of abnormal blood and/or lymphatic vessels with weak endothelial cell proliferation. The recent update of this classification includes genetic knowledge that has rapidly accumulated during the past 10–20 years. In parallel, targeted molecular therapies have started to emerge.

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