Sirolimus for Venous Malformations: A Systematic Review of Efficacy and Safety

Abstract

Background:

Venous malformations can cause substantial morbidity and long-term complications. There are no Food and Drug Administration (FDA)-approved therapies for the treatment of venous malformations. However, off-label use of sirolimus has demonstrated clinical benefit in these patients. This systematic review evaluates the efficacy and safety of sirolimus in the management of venous malformations.

Methods and Results:

A systematic literature search identified 26 studies comprising 98 patients treated with sirolimus for venous malformations. Most studies were case reports or case series (77%), with 15% prospective trials and 8% retrospective analyses. Sirolimus, primarily administered orally, yielded some level of clinical improvement in 72% of reported patients, with consistent symptomatic relief observed in coagulopathy, bleeding, anemia, pain, and improved function. However, reduction in the size of the malformation varied and treatment-limiting side effects were observed.

Conclusions:

Oral sirolimus is a promising treatment option for venous malformations, especially for those with deep venous malformations. A direct, targeted topical treatment could provide clinical benefit for the cutaneous manifestation without the risk of off-target effects as occur with oral sirolimus. Further prospective, controlled studies are warranted to elucidate sirolimus’s role in managing venous malformations.

Keywords

venous malformations sirolimus phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)signaling pathway vascular anomalies systemic therapy

Introduction

Venous malformations are the most common congenital slow-flow vascular anomaly with an estimated prevalence of 45 cases per 100,000 births.¹ They can result in substantial morbidity and severe long-term complications. Venous malformations typically manifest as collections of ectatic venous channels involving the head, neck, limbs, and trunk, often with a cutaneous manifestation, but lesions may also emerge in portions of the internal viscera including the gastrointestinal tract.^2,3 There are no Food and Drug Administration (FDA) approved therapies for venous malformations.

With a highly variable clinical presentation, venous malformations usually manifest as isolated lesions, but may involve regional or multifocal lesions associated with segmental overgrowth syndromes, including blue rubber bleb nevus syndrome and Klippel–Trenaunay syndrome, among others.^4,5

Venous malformations present with deformity, bleeding, infection, chronic pain, and functional limits. Interventional treatments—surgery, sclerotherapy, and laser therapy, for instance—may be inadequate, particularly in patients with extensive, cutaneous, or invasive disease, highlighting an unmet clinical need for pharmacologic options.^2,6

Recent advances in our understanding of the pathogenesis of venous malformations have implicated abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, a critical intercellular pathway that plays a central role in venous malformation expansion and proliferation.^6,7 The PI3K/AKT/mTOR signaling pathway overactivation that underlies the pathogenesis of venous malformations mostly results from somatic over activating mutations in Tyrosine Kinase with Immunoglobulin and EGF Homology Domains-2 (TIE2)/TEK gene and from PIK3CA gene hyperactivating variants. In the first murine model of a human venous malformation, researchers induced endothelial cell tyrosine kinase receptor TIE2 mutations in mice.⁸ These mutations triggered venous malformations with ectatic blood-filled channels that enlarged over time. Using this model, daily intraperitoneal sirolimus injections over 7 days prevented venous malformation growth and attenuated mutant TIE2-induced signaling. Sirolimus, an mTOR inhibitor, dampens PI3K/AKT/mTOR signaling, thus garnering increasing attention as a potential therapeutic option for venous malformations.^7–9 This systematic review examines clinical study findings related to the role of sirolimus in the treatment of children and adults with venous malformations.

Methods

Search strategy

The primary objective of the search was to identify and assess clinical studies published within a 10-year period (January 2014–January 2024), specifically focusing on the role of sirolimus in the treatment of venous malformations. The search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁰ All studies were assessed to ensure they contained clinical data on patients treated with sirolimus for venous malformations. The search terms included several syndromes commonly associated with the development of venous malformations to maximize the number of patients identified who received sirolimus for venous malformations.⁴

Search criteria

All searches included clinical signs and syndromes and a drug term with the connector “AND” (Table 1). For example, the search format was as follows: “venous malformation” AND “sirolimus” OR “rapamycin” OR “mTOR inhibitor.” Only studies published in English with titles and/or abstracts indicating clinical data directly related to sirolimus in the treatment of patients with venous malformations were included.

Table 1.

Search Delimiters

Years	January 3, 2014–January 3, 2024
Terms	Clinical signs Venous malformation Capillary lymphatic venous malformation Syndromes associated with venous malformations: Banayan-Riley-Ruvalcaba Blue rubber bleb nevus CLOVES Klippel–Trenaunay Maffucci Proteus Servelle–Martorell	Drugs Sirolimus Rapamycin mTOR inhibitor
Parameters	All searches included a clinical sign or syndrome term and a drug term. The search used the connector word “and” to return findings (e.g., “venous malformation” AND “sirolimus”).
Sources (databases)	PubMed Google Scholar Cochrane Reviews
Inclusion criteria (study types)	Case reports or series Clinical trials (all) Meta-analyses Review articles
Study selection	Must have contained clinical data directly related to sirolimus (rapamycin or mTOR inhibitor) in the treatment of venous malformations—that is, the study included patients with a venous malformation treated with sirolimus
Languages	English
Notes	Studies from the initial “hits” were reviewed to ensure they met all inclusion criteria.

Data extraction

From each relevant study, pertinent details were extracted and compiled into a comprehensive table (Table 2). The extracted information captured study type, demographic characteristics, prior treatments for venous malformation, diagnosis and affected anatomical sites, major symptoms, sirolimus dosing and treatment duration, sirolimus efficacy, and sirolimus-related adverse events (AEs).

Table 2.

Study Summaries

Author (primary)	Study type	#Subjects sex/age	Previous treatment	Diagnosis and site affected	Major symptoms	Sirolimus route/dose	# Patients with clinical improvement/Efficacy Outcomes	Treatment length	AEs S-related
Abdelbaky, 2020¹¹	Case report	1 Male/21 months	Propranolol	VM/perineum, pelvis	Bleeding, skin lesion	Oral: 2 mg/m² TSTL: 5–10 ng/m	1 ↓ bleeding ↓ straining at defecation ↓ skin lesions ↓ pain Deep pelvic aspect of VM not changed	5 months, with clinical improvement at 1 week	NR
Aksu, 2017¹²	Case report	1 Male/11 years	Propranolol	BRBNS/vascular lesion in the fundus mucosa, dermatologic nodules, angioma in occipital lobe	Anemia, vascular and skin lesions	Oral: 0.1 mg/kg (2.5 mg/d) TSTL: 1–5 ng/mL	1 ↓ anemia ↓ lesions on tongue and fundus ↑ QoL No change in skin or brain lesions	20 months (improvement at 2.5 months)	Episodic oral mucositis resulted in dose reduction to 0.5 mg OD
Akyuz, 2017¹³	Case report	1 Female/6 years	Steroids, interferon	BRBNS with multiple VMs	Pain, anemia	Oral: 2 mg/m² QD TSTL: 5–12 ng/mL	1 ↓ bleeding ↓ anemia ↓ lesion size Stable cutaneous lesions after treatment	4 months	NR
AlNooh, 2021¹⁴	Case report	1 Female/18 years	Radiation, cyclosporin, vincristine	BRBNS with multifocal VM	Bleeding (GI), anemia	Oral: 1 mg increased to 2 mg/QD	1 Increased dose to 2 mg/day resulted in: ↓ lesion size and number (lower left neck) ↓ anemia ↓ bleeding	5 months at 2 mg/day	NR
Cardoso, 2016¹⁵	Case report	1 Male/19 years	Surgery	BRBNS/multiple visceral, muscular, and subcutaneous vascular lesions	Pain, disfigurement, GI bleeding requiring frequent transfusions	Oral: 2 g/day	1 ↓ subcutaneous/muscular lesions Anemia resolved No change in size of vascular lesions	1 year (noticeable improvement after 5 months treatment)	NR
Chang, 2022¹⁶	Case report	1 Female/1 week	No	BRBNS/lesions head, trunk, and limbs, oral mucosa, and vagina	Lesions	Low-dose sirolimus (dose not specified) TSTL: 4.5–12 ng/mL	1 ↓ lesion size ↓ swelling	5 years	NR
Fernández, 2019¹⁷	Case report	1 Male/21 years	Surgery, octreotide	BRBNS/multiple dermatologic lesions, GI, and liver lesions	Anemia, GI bleeding	Oral: 0.07 mg/kg (5 mg/QD)	1 ↓ anemia (Hb increased from 8.5 to 12 g/dL) ↓ bleeding	2 years	NR
Ferres-Ramis, 2015¹⁸	Case report	1 NA/6 years	Laser ablation	BRBNS with intestinal VMs	Intestinal bleeding, anemia, skin lesions	Oral: 0.025 mg/kg	1 ↓ anemia (Hb normalized within 30 of sirolimus treatment) No further need for transfusions Skin lesions improved slightly	12 months	NR
Ghanam, 2022¹⁹	Case report	1 NA/3 years	Propranolol, transfusions, sclerotherapy	BRBNS with diffuse cutaneous venous angiomas affecting whole body	Angioma, rectal bleeding	NA: 2 mg/m²	1 ↓ angioma size ↓ bleeding (no episodes of bleeding)	18 months	NR
Goldenberg, 2017²⁰	Case report	1 Female/19 years	Resection	VM/giant soft tissue mass compromising the entire left hemithorax	Enlargement, bleeding	Oral: 0.6 mg/m² BID TSTL: 10–15 ng/mL	1 ↓ lesion volume ↓ pain After 2 years, lesion volume decreased sufficiently to permit surgery 6 months after surgery, patient was asymptomatic and had improved QoL while continuing sirolimus	≥2 years (noticeable improvement at 6 months)	NR
Hammer, 2018¹⁷	Prospective study	74 Female/18–64 years	Sclerotherapy, surgical resection	Sporadic VM (6), capillary VM (1) All refractory to standard care	Pain, oozing, bleeding	Oral: 0.8 mg/m² BID TSTL: 10–15 ng/mL	6 ↓ bleeding ↑ physical functioning ↓ pain No symptom improvement (1) No malformation improvement or progression (2) After 1 year of sirolimus treatment, all evaluable patients with VM (5) experienced reduced pain and 3 experienced malformation shrinkage	1–48 months	1 patient stopped treatment at 1 month due to serious mucositis
Ji, 2021²¹	Prospective study, phase 2	19 NA/0–4 years	Partial resection or sclerotherapy or embolization or laser therapy	Serious VM impinging on a vital structure	Lesions, pain, functional limitations	Oral: 0.8 mg/m² BID TSTL: 10–15 ng/mL	16 Malformation reduction ≥25% ↓ lesion size (2)	≥12 months	Most common (mild or moderate) Mucositis Diarrhea Vomiting Rash Pneumonitis
Mack, 2019²²	Retrospective review	3 NA/1–25 years	Sclerotherapy, laser therapy	VM	Worsening symptoms, increasing size of their vascular malformations	Oral: 0.8–1 mg/m² BID TSTL: 5–15 ng/mL	3 1–3 months of starting sirolimus ↓ coagulopathy (87% experienced declining D-dimer levels)	3 months	Oral mucositis No patient required permanent discontinuation of sirolimus due to AE
Maruani, 2021²³	Multicenter, open label, observational	22 NA/11.6 years (mean)	Partial surgical resection (4), sclerotherapy (6)	VM	Bleeding, oozing, reduced QoL	Oral: 0.08 mg/kg/d BID TSTL: 4–12 ng/mL	0 ↓ bleeding ↓ oozing ↑ QOL Sirolimus treatment did not change the volume of vascular malformations detected on MRI	4–8 months	Serious AEs (single cases) Viral ileitis Septic arthritis of a toe Sepsis due to Pseudomonas aeruginosa Fecaloma Deep vein thrombosis of the leg
Ogu, 2018²⁴	Case report	1 Female/15 years	Surgical removal of multiple blebs from her stomach, small intestine, and colon; transfusions	BRBNS with upper and lower GI malformations	Oropharyngeal bleeding, anemia requiring frequent transfusions	Oral: 0.05 mg/kg TSTL: 5–10 ng/mL	1 Within 2 months of therapy: No hematochezia and melena ↓ anemia (Hb returned to normal No further need for transfusions	5 years	NR
Salloum, 2016²⁵	Retrospective review	4 3 Female/2–16 years	Transfusions (3), surgery (2), sclerotherapy (2)	BRBNS/GI and dermatologic locations including neck, chest, shoulder	Pain, lesions, bleeding, anemia	Oral: 0.8 mg/m² BID TSTL: 10–13 ng/mL	4 Lesion size and characteristics improved in all patients All patients reported a decrease in pain and improvement in QOL All 3 patients requiring transfusions became transfusion-independent Resolution of coagulopathy (1)	21 months (median) Time to response: 1.5 months treatment	Mucositis (4) Neutropenia (1): resulted in temporary treatment interruption
Seront, 2019²⁶	Pilot phase 2A trial	6 NA/14–64 years	Standard treatments not specified	VM	Elevated D-dimers, lowered QoL due to pain, bleeding, and oozing	Oral: 2 mg QD TSTL: 10–15 ng/mL	6 ↑ QoL in all patients ↓ pain, bleeding, and oozing (within first month) ↓ coagulopathy and D-dimer values 20% reduction in lesion size (5) No lesion elimination	12 months	NR
Triana, 2017²⁷	Retrospective review	4 3 Female/NA	Yes, but unspecified	VM upper or lower limb	Pain, deformity, coagulopathy (elevated D-dimer)	Oral: 0.8 mg/m² BID	4 ↓ reduction in lesion size ↓ symptoms	8.5 months (range 1–51 months)	NR
Wang, 2018²⁸	Case report	1 Female/12 years	Surgery	BRBNS/hemangiomas on back, neck, arms, legs, chest, back, and on the tip of the tongue	Anemia, hemangiomas, bleeding, coagulopathy requiring blood transfusions	Oral: 1 mg/m² (average 0.7 mg/d) Serum concentration range: 6.2–11.89 µg/L	1 ↑ Hb, normal range at 1 month of treatment No longer need for blood transfusions ↓ skin and mucosal hemangioma	1 year	NR
Warner, 2015²⁹	Case report	1 Male/18 years	Sclerotherapy, tracheostomy	BRBNS with supraglottic hemangiomas	Anemia	Oral: 4 mg/QD	1 Anemia resolved after 10 months of treatment	1 year	NR
Wataya-Kaneda, 2023³⁰	Open label, single arm	2 Male/4 and 23 years	Sclerotherapy (1), none (1)	BRBNS/dermatologic sites, including thigh, buttock, leg	Pain	Topical: 0.2% sirolimus gel BID Blood sirolimus concentration below the limit of measurement	1 ↓ pain Mild lesion improvement	12 weeks	NR
Weiss, 2021³¹	Case report	1 Female/2 years	Propranolol	BRBNS/hemarthrosis of her right knee recurrence of the preexisting nuchal subcutaneous malformation	GI hemorrhage, requiring multiple blood transfusions, anemia, elevated D-dimer	Oral: 0.1–0.2 mg/kg/d TSTL: 8–10 ng/mL	1 ↑ Hb levels No need for further transfusions ↓ D-dimer levels	9 years	Hyperlipidemia
Yang, 2021³²	Case report	1 Female/38 days	Transfusions, hemostatic agents	BRBNS with lesions in the right lobe of the liver	Anemia, multiple dark blue skin lesions, bleeding (hematochezia)	Oral: 0.95 mg/m²/day TSTL: 10–15 ng/mL	1 ↓ Anemia (hemoglobin returned to normal after 4 days of treatment) Transfusion independent ↓ Bleeding (negative fecal occult blood test and GI bleeding controlled) ↓ skin lesions No need for blood transfusion, but iron supplementation needed	28 months	NR
Zhai, 2022³³	Case report	1 Female/56 years	Transfusion, hemostatic treatment	BRBNS with multiple blue hemangiomas protruding from the skin	Melena, internal hemorrhage	Oral: 1 mg/QD	1 Melena resolved after 1 month of treatment No evidence of internal bleeding No need for transfusions after 6 months of treatment ↓ lesions after 1 year of treatment	12 months	NR
Zhang, 2022³⁴	Case report	4 1 Female/10 months — 9 years	Surgery, laser therapy, propranolol	BRBNS/GI tract and dermatologic sites including tongue and torso	Anemia	Oral: 1.0–1.5 mg/m²/day TSTL: 5–10 ng/mL	4 All patients responded; median 7.5 weeks ↓ dermatologic lesion size ↓ GI lesion size (2) ↓ pain (2) Dark red vessels decreased in size or disappeared ↓ D-dimer levels	7–22 months	Mucositis (mild or moderate, all patients)
Zhou, 2021³⁵	Prospective study	11 7 Female/5–49 years	Sclerotherapy, argon plasma, coagulation surgery	BRBNS/widespread dermatologic and internal lesions	GI bleeding, lesions, anemia	Oral: 1.0 mg/m² TSTL: 3–10 ng/mL	11 Visible improvement in lesion size and characteristics in all patients ↑ QoL ↓ lesion size skin, viscera, and GI tract ↑ Hb levels 10 of 11 patients free of transfusion need by 15 months of treatment ↓ D-dimer decreased in 8/10 patients	>12 months	Mucositis (9) Transient elevated liver enzymes (2)

AEs, adverse events; BID, Twice a day; BRBNS, Blue Rubber Bleb Nevus Syndrome; GI, Gastrointestinal; Hb, Hemoglobin; NA, Not Applicable/Not Available; NR, Not Reported; QD, Every day; QOL, quality of life; TSTL, Target Sirolimus Trough Level; VM, Venous Malformation.

Statistical analyses

Given the inherent heterogeneity in outcome measures and subject selection criteria across the studies, formal statistical analyses were not conducted. Instead, descriptive statistical analyses were completed when necessary to enhance clarity in data presentation.

Institutional review board approval

As a retrospective review of existing literature, this study did not require formal institutional review board approval.

Results

This search strategy yielded 90 initial findings, the contents of which were scrutinized against the search delimiters. After excluding citations that did not meet the search delimiters criteria, the search yielded 26 studies that included 98 patients (Table 2).

The majority of the studies (77%, 20/26) were case reports or case series. Prospective clinical trials accounted for 15% (4/26), of which 2 were open-label, while retrospective chart analyses constituted 8% (2/26).

Demographics

The analysis included a total of 98 patients, with 2 studies (Ji,²¹ Maurani²³) accounting for 41 patients. Most studies included patients with venous malformations with cutaneous involvement, especially those studies with patients diagnosed with blue rubber bleb nevus syndrome.^{12–19,24,25,28–35} The overall age range was wide, from newborn¹⁶ to 64 years.²⁶ In studies that reported patient sex, the distribution skewed toward women, with 27 female vs 19 male patients.

Treatment

Virtually all patients had received and failed previous treatments, including surgery, sclerotherapy, and supportive transfusions. Sirolimus, primarily administered orally except for one small study using a topical formulation in two patients,³⁰ was typically administered once or twice daily to achieve target serum trough levels of 5–15 ng/mL. Treatment duration with sirolimus varied considerably, ranging from 1 month⁷ to 5 years.^16,24

Sirolimus efficacy overview

Most of the studies (69%, 18/26) were observational and did not use standardized efficacy assessment; 19% (5/26) were baseline controlled, and the remaining 12% (3/26) were retrospective.

Overall, sirolimus demonstrated some level of efficacy in the majority of reported patients, with 72% (71/98) showing evidence of clinical improvement. Sirolimus yielded consistent improvement in symptoms such as bleeding, oozing, pain, and anemia, although evidence of malformation size reduction was inconsistent.^21,23,26,35 Across the studies, there was no difference in efficacy based on mutation subtype, although not all studies reported on mutation subtype.

Symptom improvement

Improvements were noted in venous malformation symptoms such as pain, oozing, and disfigurement across studies. Additionally, functional capacity and quality of life (QoL) measurements showed improvement in several studies.^20,23,25,26 Only one study from the group of 26 examined topical sirolimus, a small (N = 2), short-term (12-week) study: both patients experienced a decrease in pain, and one exhibited some evidence of lesion improvement.³⁰ While most case reports reported improvements in lesion size, which was assessed by a variety of methods including MRI and CT, as appropriate, some did not observe clinically meaningful reductions even after prolonged treatment of up to 2 years.^{11–13,15,23}

Coagulopathy

Almost all studies showed treatment with sirolimus reduced episodes of bleeding. Sirolimus treatment resulted in improvements in coagulopathy markers, that are relevant for internal venous malformations, such as D-dimer levels^{22,26,31,34,35} and anemia.^{12,14,15,17,18,24,25}

Anemia/transfusions

In a total of 7 case reports,^{18,19,24,28,31–33} 1 prospective study,³⁵ and 1 retrospective review²⁵ involving 21 patients, the initiation of sirolimus treatment led to a resolution of anemia to the extent that transfusions were no longer necessary. Notably, in all of these studies, patients were diagnosed with blue rubber bleb nevus syndrome. Additionally, in 2 separate studies of 5 patients, a reduced need for transfusions became evident after approximately 2 months of sirolimus treatment.^24,25

Adverse events

The most frequent AE associated with sirolimus treatment was mucositis, observed in 7/26 (27%) studies, which was generally mild or moderate in severity. However, it necessitated a dose reduction in one patient¹² and study discontinuation in another patient.⁶ Other potentially relevant AEs noted included infection and neutropenia. Another study²⁵ reported serious but transient neutropenia (without infection) in one patient, resulting in only temporary discontinuation of treatment. In this study, targeted sirolimus trough levels were considered “relatively low” at 10–13 ng/mL and all patients received background antibiotic therapy. AEs were not reported in 65% (17/26) of the studies.

Discussion

The publications reviewed suggest that sirolimus may be an effective pharmacologic option in the management of internal venous malformations.^6,36,37 However, it is important to note that sirolimus is not currently FDA-approved for the treatment of any vascular anomaly, including venous malformations.⁴

Our study was the first systematic review to focus solely on the potential role of sirolimus in the management of venous malformations, a common type of vascular anomaly.⁴ Our findings confirm and extend previous findings supporting a potentially important role for sirolimus in vascular anomalies such as venous malformations, especially those impacting internal organ systems.^9,36,38 Our results suggest that oral sirolimus has the potential to improve the clinical manifestations posed by venous malformations, especially those that have extensive involvement with deeper internal structures, including coagulation, D-dimer expression, and anemia. The majority of patients (72%) showed evidence of treatment efficacy, despite an inadequate response to previous standard treatment. Sirolimus was administered orally in all but one study,³⁰ with a target blood level usually in the range of 5–15 ng/mL, which appears standard for oral treatment.^36,37

There were too few patients in our analysis to evaluate the effect of oral or topical sirolimus on the cutaneous manifestations of venous malformations such as swelling, bleeding, pain, and raised blueish lesions. However, since oral sirolimus has very low dermal penetration, a topical formulation that achieves therapeutic levels of sirolimus in the dermis may offer superior efficacy and improved tolerability in terms of fewer systemic AEs for patients with predominately dermatologic lesions.^4,39

Our literature review revealed that sirolimus treatment has been reported to provide consistent and enduring symptomatic relief for many patients with venous malformations, with improvements seen in lesion bleeding and size, pain, and enhancements in QoL assessments. In some studies, sirolimus provided continued and well-tolerated efficacy over study evaluation periods ranging from 2 to 5 years.^6,16,17,24 These findings are consistent with the interim results of the phase III Vascular Anomaly-Sirolimus-Europe trial, of oral sirolimus (serum level 10–15 ng/mL).⁴⁰ That study includes 132 patients with slow-flow vascular malformations, 74 (56%) of whom were diagnosed with a venous malformation. After treatment (54% for at least 1 year; 46% for 2 years), 85% of patients experienced at least some clinical improvement, chiefly pain reduction and function improvement. Sirolimus also exerted a rapid ameliorative effect, with 50% of patients reporting symptomatic improvement within the first month of treatment. In addition, there were no differences in efficacy noted across mutation subtypes.

Patients with venous malformation associated syndromes, especially those with rare, serious syndromes, such as some overgrowth syndromes and blue rubber bleb nevus syndrome, may experience frequent gastrointestinal bleeding and, in turn, anemia requiring transfusions.⁴¹ Sirolimus seemed to demonstrate notable efficacy in alleviating anemia and bleeding in these patients, reducing or obviating the need for transfusions.

AEs in our review were generally consistent with those previously reported with sirolimus treatment for vascular malformation.^6,36,37 Mucositis was the most common AE and resulted in one dose reduction¹² and one study discontinuation.⁶ Side effects typically associated with oral sirolimus treatment in the kidney transplant setting after 24 weeks’ treatment, including anemia, thrombocytopenia, and leukopenia, were not seen.⁴² In our analysis, evidence of serious immunosuppression such as infection or neutropenia was uncommon.

These findings, however, should be viewed in context. Most studies included were either case reports or case series and investigators have shown that the vast majority (>90%) of these study types tend to present positive results, raising the risk of overinterpretation.⁴³ In addition, there are generalizability limitations in this study due to considerable heterogeneity in study conditions, processes, and outcome assessments. These limitations obscure the interpretation of systematic reviews such as ours that rely primarily on retrospective analyses. The immunosuppressive effects of long-term, oral sirolimus treatment can result in uncommon, but potentially concerning, AEs, such as an increased risk for serious infections.²⁶ This risk has likely hampered the widespread use of oral sirolimus. For the above reasons, caution should be used in interpreting the results of our analysis, especially AE rates. Further work is needed to characterize the safety and efficacy of sirolimus in treating both cutaneous and internal venous malformations.

Conclusion

Together, our findings suggest that sirolimus is an important therapy in the management of venous malformations regardless of underlying mutations. However, due to the retrospective nature of this review and the heterogeneity of the many case studies included, the current findings, although intriguing, should be considered an impetus for future prospective, controlled studies to clarify the role of sirolimus in the management of symptomatic venous malformations. Furthermore, differences in responses to treatment and a potential relationship to the type and location of the disease is an area that merits future examination.

Sirolimus appears to be a valuable addition to the armamentarium for the management of venous malformations, especially those located internally. Although controlled studies are still needed, the preponderance of findings to date, as captured in our study, suggests that sirolimus can be effective and well tolerated in a patient population in need of alternative treatment options.

Authors’ Contributions

J.T.: Conceptualization, writing, and analysis. J.M.: Conceptualization, writing, and analysis. M.K.: Conceptualization, writing, and analysis. M.T.: Conceptualization, writing, and analysis. A.G.: Formal analysis.

Footnotes

Acknowledgment

The authors would like to thank Encompass Communications and Learning, Inc., for their editorial assistance in the development of this article.

Author Disclosure Statement

J.T., M.K. are consultants to Palvella Therapeutics. J.M. is an employee of Palvella Therapeutics. The other authors do not have any disclosures.

Funding Information

Dr. Martini is an employee of Palvella Therapeutics, that sponsors the project. Drs. Teng, Kelly and Tollefson did not receive compensation for their work related to this publication.

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